U.S. patent application number 10/622687 was filed with the patent office on 2004-04-01 for indole, azaindole and related heterocyclic ureido and thioureido piperazine derivatives.
Invention is credited to Kadow, John F., Regueiro-Ren, Alicia, Taylor, Malcolm, Xue, Qiufen May.
Application Number | 20040063746 10/622687 |
Document ID | / |
Family ID | 31188494 |
Filed Date | 2004-04-01 |
United States Patent
Application |
20040063746 |
Kind Code |
A1 |
Regueiro-Ren, Alicia ; et
al. |
April 1, 2004 |
Indole, azaindole and related heterocyclic ureido and thioureido
piperazine derivatives
Abstract
This invention provides compounds having drug and bio-affecting
properties, their pharmaceutical compositions and method of use. In
particular, the invention is concerned with ureido and thioureido
piperazine derivatives of Formula I. These compounds possess unique
antiviral activity, whether used alone or in combination with other
antivirals, antiinfectives, immunomodulators or HIV entry
inhibitors. More particularly, the present invention relates to the
treatment of HIV and AIDS. The compounds of Formula I are 1
wherein: Y is O or S; Z is 2 Q is selected from the group
consisting of 3 m is 2; A is NR.sup.13R.sup.14; and --W-- is 4
Inventors: |
Regueiro-Ren, Alicia;
(Middletown, CT) ; Xue, Qiufen May; (Thousand
Oaks, CT) ; Kadow, John F.; (Wallingford, CT)
; Taylor, Malcolm; (Didcot, GB) |
Correspondence
Address: |
STEPHEN B. DAVIS
BRISTOL-MYERS SQUIBB COMPANY
PATENT DEPARTMENT
P O BOX 4000
PRINCETON
NJ
08543-4000
US
|
Family ID: |
31188494 |
Appl. No.: |
10/622687 |
Filed: |
July 18, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60398812 |
Jul 25, 2002 |
|
|
|
Current U.S.
Class: |
514/300 ;
514/419; 546/113; 548/494 |
Current CPC
Class: |
C07D 417/12 20130101;
C07D 471/04 20130101; C07D 413/04 20130101; C07D 209/14
20130101 |
Class at
Publication: |
514/300 ;
514/419; 546/113; 548/494 |
International
Class: |
C07D 471/02; A61K
031/4745; A61K 031/405; C07D 209/18 |
Claims
What is claimed is:
1. A compound of Formula I, including pharmaceutically acceptable
salts thereof, 105wherein: Y is O or S; Z is 106Q is selected from
the group consisting of 107R.sup.1 is hydrogen; R.sup.2 is
hydrogen, methoxy or halogen; R.sup.3, R.sup.4, and R.sup.5, are
independently selected from the group consisting of hydrogen,
halogen, cyano, nitro, COOR.sup.8, XR.sup.9, and B; m is 2; R.sup.6
is O or does not exist; R.sup.7 is hydrogen or methyl; --represents
a carbon-carbon bond; A is NR.sup.13R.sup.14; R.sup.13 and R.sup.14
are independently selected from the group consisting of hydrogen,
(C.sub.1-6)alkyl and phenyl; wherein said (C.sub.1-6)alkyl and
phenyl are independently optionally substituted with one to three
same or different halogens or from one to three same or different
substituents selected from F; or R.sup.13 and R.sup.1.sup.4 taken
together with the nitrogen atom to which they are attached forms a
heteroalicyclic ring containing 4 to 6 atoms; heteroaryl is
selected from the group consisting of pyridinyl, pyrazinyl,
pyridazinyl, pyrimidinyl, furanyl, thienyl, benzothienyl,
thiazolyl, isothiazolyl, oxazolyl, benzooxazolyl, isoxazolyl,
imidazolyl, benzoimidazolyl, 1H-imidazo[4,5-b]pyridin-2-yl,
1H-imidazo[4,5-c]pyridin-2-yl, oxadiazolyl, thiadiazolyl,
pyrazolyl, tetrazolyl, tetrazinyl, triazinyl, triazolyl,
quinolinyl, and isoquinolyl; heteroalicyclic ring is selected from
the group consisting of azetidinyl, piperidyl, piperazinyl,
morpholinyl, pyrrolidinyl, thiomorpholinyl and tetrahydropyranyl;
--W-- is 108R.sup.15, R.sup.16, R.sup.17, R.sup.18, R.sup.19,
R.sup.20, R.sup.21, R.sup.22 are each independently H or
(C.sub.1-6) alkyl; wherein (C.sub.1-6)alkyl is optionally
substituted with one to three same or different members selected
from the group consisting of halogen; with the proviso that a
maximum of two of R.sup.15, R.sup.16, R.sup.17, R.sup.18, R.sup.19,
R.sup.20, R.sup.21, R.sup.22 are not hydrogen; B is selected from
the group consisting of (C.sub.1-6)alkyl, (C.sub.3-6)cycloalkyl,
C(O)NR.sup.23R.sup.24, phenyl and heteroaryl; wherein said
(C.sub.1-6)alkyl, phenyl and heteroaryl are independently
optionally substituted with one to three same or different halogens
or from one to three same or different substituents selected from
F; F is selected from the group consisting of (C.sub.1-6)alkyl,
phenyl, hydroxy, (C.sub.1-6)alkoxy, halogen, benzyl,
--NR.sup.25C(O)--(C.sub.1-6)alkyl, --NR.sup.26R.sup.27, COOR.sup.28
and --CONR.sup.29R.sup.30; wherein said (C.sub.1-6)alkyl is
optionally substituted with one to three same or different halogen;
R.sup.8, R.sup.9 and R.sup.28 are selected from the group
consisting of hydrogen and (C.sub.1-6)alkyl; X is selected from the
group consisting of NR.sup.31, O and S; and R.sup.23, R.sup.24,
R.sup.25, R.sup.26, R.sup.27, R.sup.29, R.sup.30, R.sup.31 are
independently selected from the group consisting of hydrogen,
(C.sub.1-6)alkyl, (C.sub.1-6)alkoxy, phenyl and heteroaryl; wherein
said phenyl and heteroaryl are independently optionally substituted
with one to three same or different halogen, methyl, or CF.sub.3
groups; with the proviso that when Q is 109R.sup.2 and R.sup.4,
cannot both be hydrogen; and with the further proviso that when Q
is 110then R.sup.2 and R.sup.5, cannot both be hydrogen.
2. A compound of claim 1, wherein: R.sup.15, R.sup.16, R.sup.17,
R.sup.18, R.sup.19, R.sup.20, R.sup.21, R.sup.22 are each
independently H or methyl; wherein only one or zero of R.sup.15,
R.sup.16, R.sup.17, R.sup.18, R.sup.19, R.sup.20, R.sup.21 and
R.sup.22 is methyl; Y is O; and Q is a member selected from groups
(A) and (B) consisting of 111provided R.sup.3 and R.sup.4 are each
hydrogen; and R.sup.5 is selected from the group consisting of
halogen, cyano, methoxy, COOR.sup.8, C(O)NHCH.sub.3,
C(O)NHheteroaryl, and heteroaryl; and 112provided R.sup.3 is
hydrogen; R.sup.4 is selected from the group consisting of
hydrogen, halogen, methoxy, cyano, COOR.sup.8, C(O)NHCH.sub.3,
C(O)NHheteroaryl and heteroaryl; and R.sup.6does not exist.
3. A compound of claim 2 wherein R.sup.13 and R.sup.14 are
independently selected from the group consisting of hydrogen,
(C.sub.1-6)alkyl and phenyl; or taken together with the nitrogen
atom to which they are attached forms a pyrrolidinyl or morpholinyl
ring.
4. A compound of claim 3 in which Q is a member selected from
groups (A) and (B) consisting of 113provided R.sup.2 is methoxy or
halogen; and R.sup.5 is selected from the group consisting of
methoxy, C(O)NH.sub.2, C(O)NHCH.sub.3, C(O)NHheteroaryl, and
heteroaryl; and 114provided R.sup.2 is methoxy or halogen; R.sup.4
is selected from the group consisting of methoxy, C(O)NH.sub.2,
C(O)NHCH.sub.3, C(O)NHheteroaryl and heteroaryl; and heteroaryl is
oxadiazolyl, triazolyl, pyrazolyl, thiazolyl, pyrazinyl or
oxazolyl.
5. A compound of claim 4 wherein: R.sup.13 and R.sup.14 are each
methyl.
6. A compound of claim 4 wherein: R.sup.13 and R.sup.14 taken
together with the nitrogen atom to which they are attached form a
morpholinyl ring.
7. A compound of claim 5 wherein: Q is 115and R.sup.5 is selected
from the group consisting of methoxy, C(O)NHCH.sub.3, and
heteroaryl.
8. A compound of claim 6 wherein: Q is 116and R.sup.5 is selected
from the group consisting of C(O)NHCH.sub.3 and heteroaryl.
9. A compound of claim 5 wherein: Q is 117R.sup.4 is selected from
the group consisting of C(O)NHCH.sub.3 and heteroaryl; and
heteroaryl is oxadiazolyl, triazolyl, pyrazolyl, thiazolyl,
pyrazinyl or oxazolyl.
10. A compound of claim 6 wherein: Q is 118R.sup.4 is selected from
the group consisting of C(O)NHCH.sub.3 and heteroaryl; and
heteroaryl is oxadiazolyl, triazolyl, pyrazolyl, thiazolyl,
pyrazinyl or oxazolyl.
11. A pharmaceutical composition which comprises an antiviral
effective amount of a compound of Formula I, including
pharmaceutically acceptable salts thereof, as claimed in claim 1,
and one or more pharmaceutically acceptable carriers, excipients or
diluents.
12. The pharmaceutical composition of claim 11, useful for treating
infection by HIV, which additionally comprises an antiviral
effective amount of an AIDS treatment agent selected from the group
consisting of: (a) an AIDS antiviral agent; (b) an anti-infective
agent; (c) an immunomodulator; and (d) HIV entry inhibitors.
13. A method for treating a mammal infected with the HIV virus
comprising administering to said mammal an antiviral effective
amount of a compound of Formula I, including pharmaceutically
accceptable salts thereof, as claimed in claim 1, and one or more
pharmaceutically acceptable carriers, excipients or diluents.
14. The method of claim 13, comprising administering to said mammal
an antiviral effective amount of a compound of Formula I, including
pharmaceutically acceptable salts thereof, in combination with an
antiviral effective amount of an AIDS treatment agent selected from
the group consisting of: an AIDS antiviral agent; an anti-infective
agent; an immunomodulator; and an HIV entry inhibitor.
Description
REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
Application Serial No. 60/398,812 filed Jul. 25, 2002.
FIELD OF THE INVENTION
[0002] This invention provides compounds having drug and
bio-affecting properties, their pharmaceutical compositions and
method of use. In particular, the invention is concerned with new
heterocyclic ureido and thioureido piperazines derivatives that
possess unique antiviral activity. More particularly, the present
invention relates to compounds useful for the treatment of HIV and
AIDS.
BACKGROUND ART
[0003] HIV-1 (human immunodeficiency virus-1) infection remains a
major medical problem, with an estimated 42 million people infected
worldwide at the end of 2002. The number of cases of HIV and AIDS
(acquired immunodeficiency syndrome) has risen rapidly. In 2002,
.about.5.0 million new infections were reported, and 3.1 million
people died from AIDS. Currently available drugs for the treatment
of HIV include nine nucleoside reverse transcriptase (RT)
inhibitors or approved single pill combinations(zidovudine or AZT
(or Retrovir.RTM.), didanosine (or Videx .RTM.), stavudine (or
Zerit.RTM.), lamivudine (or 3TC or Epivir.RTM.), zalcitabine (or
DDC or Hivid.RTM.), abacavir succinate (or Ziagen.RTM.), Tenofovir
disoproxil fumarate salt (or Viread.RTM.), Combivir.RTM. (contains
-3TC plus AZT), Trizivir.RTM. (contains abacavir, lamivudine, and
zidovudine); three non-nucleoside reverse transcriptase inhibitors:
nevirapine (or Viramune.RTM.), delavirdine (or Rescriptor.RTM.) and
efavirenz (or Sustiva.RTM.), and eight peptidomimetic protease
inhibitors or approved formulations: saquinavir, indinavir,
ritonavir, nelfinavir, amprenavir, lopinavir, Kaletra.RTM.
(lopinavir and Ritonavir), and Atazanavir (Reyataz.RTM.). Each of
these drugs can only transiently restrain viral replication if used
alone. However, when used in combination, these drugs have a
profound effect on viremia and disease progression. In fact,
significant reductions in death rates among AIDS patients have been
recently documented as a consequence of the widespread application
of combination therapy. However, despite these impressive results,
30 to 50% of patients ultimately fail combination drug therapies.
Insufficient drug potency, non-compliance, restricted tissue
penetration and drug-specific limitations within certain cell types
(e.g. most nucleoside analogs cannot be phosphorylated in resting
cells) may account for the incomplete suppression of sensitive
viruses. Furthermore, the high replication rate and rapid turnover
of HIV-1 combined with the frequent incorporation of mutations,
leads to the appearance of drug-resistant variants and treatment
failures when sub-optimal drug concentrations are present (Larder
and Kemp; Gulick; Kuritzkes; Morris-Jones et al; Schinazi et al;
Vacca and Condra; Flexner; Berkhout and Ren et al; (Ref. 6-14)).
Therefore, novel anti-HIV agents exhibiting distinct resistance
patterns, and favorable pharmacokinetic as well as safety profiles
are needed to provide more treatment options.
[0004] Currently marketed HIV-1 drugs are dominated by either
nucleoside reverse transcriptase inhibitors or peptidomimetic
protease inhibitors. Non-nucleoside reverse transcriptase
inhibitors (NNRTIs) have recently gained an increasingly important
role in the therapy of HIV infections (Pedersen & Pedersen, Ref
15). At least 30 different classes of NNRTI have been described in
the literature (De Clercq, Ref. 16) and several NNRTIs have been
evaluated in clinical trials. Dipyridodiazepinone (nevirapine),
benzoxazinone (efavirenz) and bis(heteroaryl) piperazine
derivatives (delavirdine) have been approved for clinical use.
However, the major drawback to the development and application of
NNRTIs is the propensity for rapid emergence of drug resistant
strains, both in tissue cell culture and in treated individuals,
particularly those subject to monotherapy. As a consequence, there
is considerable interest in the identification of NNRTIs less prone
to the development of resistance (Pedersen & Pedersen, Ref 15).
A recent overview of non-nucleoside reverse transcriptase
inhibitors: perspectives on novel therapeutic compounds and
strategies for the treatment of HIV infection has appeared
(Buckheit, reference 99). A review covering both NRTI and NNRTIs
has appeared (De clercq, reference 100). An overview of the current
state of the HIV drugs has been published (De clercq, reference
101).
[0005] Several indole derivatives including indole-3-sulfones,
piperazino indoles, pyrazino indoles, and
5H-indolo[3,2-b][1,5]benzothiazepine derivatives have been reported
as HIV-1 reverse transciptase inhibitors (Greenlee et al, Ref. 1;
Williams et al, Ref. 2; Romero et al, Ref. 3; Font et al, Ref. 17;
Romero et al, Ref. 18; Young et al, Ref. 19; Genin et al, Ref. 20;
Silvestri et al, Ref. 21). Indole 2-carboxamides have also been
described as inhibitors of cell adhesion and HIV infection
(Boschelli et al, U.S. Pat. No. 5,424,329, Ref. 4). 3-substituted
indole natural products (Semicochliodinol A and B,
didemethylasterriquinone and isocochliodinol) were disclosed as
inhibitors of HIV-1 protease (Fredenhagen et al, Ref. 22).
[0006] Structurally related aza-indole amide derivatives have been
disclosed previously (Kato et al, Ref 23; Levacher et al, Ref. 24;
Dompe Spa, WO-09504742, Ref. 5(a); SmithKline Beecham PLC,
WO-09611929, Ref. 5(b); Schering Corp., U.S. Pat. No. 05023265,
Ref. 5(c)). However, these structures differ from those claimed
herein in that they are aza-indole mono-amide rather than
unsymmetrical aza-indole piperazine ureido and thioureido
derivatives, and there is no mention of the use of these compounds
for treating viral infections, particularly HIV. Indole and
azaindole piperazine containing derivatives have been disclosed in
four different PCT and issued U.S. patent applications (Reference
93-95, 106). PCT International Patent Application WO9951224 by
Bernd Nickel et. al. (reference 107) describes N-indolylglyoxamides
for the treatment of cancer. The substitution patterns on the
piperazine are outside the scope of the indoles covered by this
invention. A patent application describing a method for treating
cystic fibrosis (Reference 108) describes the use of indole
containing compounds which are generally somewhat similar to those
in reference 107 and this art is included for completeness.
[0007] None of these applications discloses ureido and thioureido
piperazines compounds such as described in this invention for the
treatment of antiviral diseases and HIV.
[0008] Nothing in these references can be construed to disclose or
suggest the novel compounds of this invention and their use to
inhibit HIV infection.
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SUMMARY OF THE INVENTION
[0117] The present invention comprises compounds of Formula I,
their pharmaceutical formulations, and their use in patients
suffering from or susceptible to a virus such as HIV. The compounds
of Formula I, which include nontoxic pharmaceutically acceptable
salts and/or hydrates thereof, have the formula and meaning as
described below. Each embodiment of a particular aspect of the
invention depends from the preceding embodiment unless otherwise
stated.
[0118] The present invention comprises compounds of Formula I, or
pharmaceutically acceptable salts thereof, which are effective
antiviral agents, particularly as inhibitors of HIV.
[0119] A first embodiment of the invention are compounds of Formula
I, including pharmaceutically acceptable salts thereof, 5
[0120] wherein:
[0121] Y is O or S;
[0122] Z is 6
[0123] Q is selected from the group consisting of 7
[0124] R.sup.1 is hydrogen;
[0125] R.sup.2 is hydrogen, methoxy or halogen;
[0126] R.sup.3, R.sup.4, and R.sup.5, are independently selected
from the group consisting of hydrogen, halogen, cyano, nitro,
COOR.sup.8, XR.sup.9, and B;
[0127] m is 2;
[0128] R.sup.6 is O or does not exist;
[0129] R.sup.7 is hydrogen or methyl;
[0130] --represents a carbon-carbon bond;
[0131] A is NR.sup.13R.sup.14;
[0132] R.sup.13 and R.sup.14 are independently selected from the
group consisting of hydrogen, (C.sub.1-6)alkyl and phenyl; wherein
said (C.sub.1-6)alkyl and phenyl are independently optionally
substituted with one to three same or different halogens or from
one to three same or different substituents selected from F; or
R.sup.13 and R.sup.14 taken together with the nitrogen atom to
which they are attached forms a heteroalicyclic ring containing 4
to 6 atoms;
[0133] heteroaryl is selected from the group consisting of
pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, furanyl, thienyl,
benzothienyl, thiazolyl, isothiazolyl, oxazolyl, benzooxazolyl,
isoxazolyl, imidazolyl, benzoimidazolyl,
1H-imidazo[4,5-b]pyridin-2-yl, 1H-imidazo[4,5-c]pyridin-- 2-yl,
oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, tetrazinyl,
triazinyl, triazolyl, quinolinyl, and isoquinolyl;
[0134] heteroalicyclic ring is selected from the group consisting
of azetidinyl, piperidyl, piperazinyl, morpholinyl, pyrrolidinyl,
thiomorpholinyl and tetrahydropyranyl;
[0135] --W-- is 8
[0136] R.sup.15, R.sup.16, R.sup.17, R.sup.18, R.sup.19, R.sup.20,
R.sup.21, R.sup.22 are each independently H or
(C.sub.1-6)alkyl;
[0137] wherein (C.sub.1-6)alkyl is optionally substituted with one
to three same or different members selected from the group
consisting of halogen; with the proviso that a maximum of two of
R.sup.15, R.sup.16, R.sup.17, R.sup.18, R.sup.19, R.sup.20 ,
R.sup.21 , R.sup.22 are not hydrogen;
[0138] B is selected from the group consisting of (C.sub.1-6)alkyl,
(C.sub.3-6)cycloalkyl, C(O)NR.sup.23R.sup.24, phenyl and
heteroaryl; wherein said (C.sub.1-6)alkyl, phenyl and heteroaryl
are independently optionally substituted with one to three same or
different halogens or from one to three same or different
substituents selected from F;
[0139] F is selected from the group consisting of (C.sub.1-6)alkyl,
phenyl, hydroxy, (C.sub.1-6)alkoxy, halogen, benzyl,
--NR.sup.25C(O)--(C.sub.1-6)alkyl, --NR.sup.26R.sup.27, COOR.sup.28
and --CONR.sup.29R.sup.30; wherein said (C.sub.1-6)alkyl is
optionally substituted with one to three same or different
halogen;
[0140] R.sup.8, R.sup.9 and R.sup.28 are selected from the group
consisting of hydrogen and (C.sub.1-6)alkyl;
[0141] X is selected from the group consisting of NR.sup.31, O and
S; and
[0142] R.sup.23, R.sup.24, R.sup.25, R.sup.26, R.sup.27, R.sup.29,
R.sup.30, R.sup.31 are independently selected from the group
consisting of hydrogen, (C.sub.1-6)alkyl, (C.sub.1-6)alkoxy, phenyl
and heteroaryl; wherein said phenyl and heteroaryl are
independently optionally substituted with one to three same or
different halogen, methyl, or CF.sub.3 groups; with the proviso
that when Q is 9
[0143] then
[0144] R.sup.2 and R.sup.4, cannot both be hydrogen; and
[0145] with the further proviso that when Q is 10
[0146] then
[0147] R.sup.2 and R.sup.5, cannot both be hydrogen.
[0148] A preferred embodiment of the invention are compounds
wherein:
[0149] R.sup.15, R.sup.16, R.sup.17, R.sup.18, R.sup.19, R.sup.20,
R.sup.21, R.sup.22 are each independently H or methyl; wherein only
one or zero of R.sup.15, R.sup.16, R.sup.17, R.sup.18, R.sup.19,
R.sup.20, R.sup.21 and R.sup.22 is methyl;
[0150] Y is O; and
[0151] Q is a member selected from groups (A) and (B) consisting of
11
[0152] provided R.sup.3 and R.sup.4 are each hydrogen; and
[0153] R.sup.5 is selected from the group consisting of halogen,
cyano, methoxy, COOR.sup.8, C(O)NHCH.sub.3, C(O)NHheteroaryl, and
heteroaryl; and 12
[0154] provided R.sup.3 is hydrogen;
[0155] R.sup.4 is selected from the group consisting of hydrogen,
halogen, methoxy, cyano, COOR.sup.8, C(O)NHCH.sub.3,
C(O)NHheteroaryl and heteroaryl; and R.sup.6does not exist.
[0156] Another preferred embodiment are compounds wherein:
[0157] R.sup.13 and R.sup.14 are independently selected from the
group consisting of hydrogen, (C.sub.1-6)alkyl and phenyl; or taken
together with the nitrogen atom to which they are attached forms a
pyrrolidinyl or morpholinyl ring.
[0158] Another embodiment of the present invention is a method for
treating mammals infected with a virus, wherein said virus is HIV,
comprising administering to said mammal an antiviral effective
amount of a compound of Formula I, including pharmaceutically
acceptable salts thereof, and one or more pharmaceutically
acceptable carriers, excipients or diluents; optionally the
compound of Formula I, including said salts thereof, can be
administered in combination with an antiviral effective amount of
an AIDS treatment agent selected from the group consisting of: (a)
an AIDS antiviral agent; (b) an anti-infective agent; (c) an
immunomodulator; and (d) HIV entry inhibitors.
[0159] Another embodiment of the present invention is a
pharmaceutical composition comprising an antiviral effective amount
of a compound of Formula I, including pharmaceutically acceptable
salts thereof, and one or more pharmaceutically acceptable
carriers, excipients, diluents and optionally in combination with
an antiviral effective amount of an AIDS treatment agent selected
from the group consisting of: (a) an AIDS antiviral agent; (b) an
anti-infective agent; (c) an immunomodulator; and (d) HIV entry
inhibitors.
DETAILED DESCRIPTION OF THE INVENTION
[0160] Since the compounds of the present invention, may possess
asymmetric centers and therefore occur as mixtures of diastereomers
and enantiomers, the present invention includes the individual
diastereoisomeric and enantiomeric forms of the compounds of
Formula I in addition to the mixtures thereof.
Definitions
[0161] The term "C.sub.1-6 alkyl" as used herein and in the claims
(unless specified otherwise) mean straight or branched chain alkyl
groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
t-butyl, amyl, hexyl and the like.
[0162] "Halogen" refers to chlorine, bromine, iodine or
fluorine.
[0163] An "aryl" group refers to an all carbon monocyclic or
fused-ring polycyclic (i.e., rings which share adjacent pairs of
carbon atoms) groups having a completely conjugated pi-electron
system. Examples, without limitation, of aryl groups are phenyl,
napthalenyl and anthracenyl. The aryl group may be substituted or
unsubstituted. When substituted the substituted group(s) is
preferably one or more selected from alkyl, cycloalkyl, aryl,
heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy,
heteroaryloxy, heteroalicycloxy, thiohydroxy, thioaryloxy,
thioheteroaryloxy, thioheteroalicycloxy, cyano, halogen, nitro,
carbonyl, O-carbamyl, N-carbamyl, C-amido, N-amido, C-carboxy,
O-carboxy, sulfinyl, sulfonyl, sulfonamido, trihalomethyl, ureido,
amino and --NR.sup.xR.sup.y, wherein R.sup.x and R.sup.y are
independently selected from the group consisting of hydrogen,
alkyl, cycloalkyl, aryl, carbonyl, C-carboxy, sulfonyl,
trihalomethyl, and, combined, a five- or six-member heteroalicyclic
ring.
[0164] As used herein, a "heteroaryl" group refers to a monocyclic
or fused ring (i.e., rings which share an adjacent pair of atoms)
group having in the ring(s) one or more atoms selected from the
group consisting of nitrogen, oxygen and sulfur and, in addition,
having a completely conjugated pi-electron system. Unless otherwise
indicated, the heteroaryl group may be attached at either a carbon
or nitrogen atom within the heteroaryl group. It should be noted
that the term heteroaryl is intended to encompass an N-oxide of the
parent heteroaryl if such an N-oxide is chemically feasible as is
known in the art. Examples, without limitation, of heteroaryl
groups are furyl, thienyl, benzothienyl, thiazolyl, imidazolyl,
oxazolyl, oxadiazolyl, thiadiazolyl, benzothiazolyl, triazolyl,
tetrazolyl, isoxazolyl, isothiazolyl, pyrrolyl, pyranyl,
tetrahydropyranyl, pyrazolyl, pyridyl, pyrimidinyl, quinolinyl,
isoquinolinyl, purinyl, carbazolyl, benzoxazolyl, benzimidazolyl,
indolyl, isoindolyl, pyrazinyl, diazinyl, pyrazine,
triazinyltriazine, tetrazinyl, and tetrazolyl. When substituted the
substituted group(s) is preferably one or more selected from alkyl,
cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy,
aryloxy, heteroaryloxy, heteroalicycloxy, thiohydroxy, thioaryloxy,
thioheteroaryloxy, thioheteroalicycloxy, cyano, halogen, nitro,
carbonyl, O-carbamyl, N-carbamyl, C-amido, N-amido, C-carboxy,
O-carboxy, sulfinyl, sulfonyl, sulfonamido, trihalomethyl, ureido,
amino, and --NR.sup.xR.sup.y, wherein R.sup.x and R.sup.y are as
defined above.
[0165] As used herein, a "heteroalicyclic" group refers to a
monocyclic or fused ring group having in the ring(s) one or more
atoms selected from the group consisting of nitrogen, oxygen and
sulfur. Rings are selected from those which provide stable
arrangements of bonds and are not intended to encomplish systems
which would not exist. The rings may also have one or more double
bonds. However, the rings do not have a completely conjugated
pi-electron system. Examples, without limitation, of
heteroalicyclic groups are azetidinyl, piperidyl, piperazinyl,
imidazolinyl, thiazolidinyl, 3-pyrrolidin-1-yl, morpholinyl,
thiomorpholinyl and tetrahydropyranyl. When substituted the
substituted group(s) is preferably one or more selected from alkyl,
cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy,
aryloxy, heteroaryloxy, heteroalicycloxy, thiohydroxy, thioalkoxy,
thioaryloxy, thioheteroaryloxy, thioheteroalicycloxy, cyano,
halogen, nitro, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl,
O-thiocarbamyl, N-thiocarbamyl, C-amido, C-thioamido, N-amido,
C-carboxy, O-carboxy, sulfinyl, sulfonyl, sulfonamido,
trihalomethanesulfonamido, trihalomethanesulfonyl, silyl, guanyl,
guanidino, ureido, phosphonyl, amino and --NR.sup.xR.sup.y, wherein
R.sup.x and R.sup.y are as defined above.
[0166] An "alkyl" group refers to a saturated aliphatic hydrocarbon
including straight chain and branched chain groups. Preferably, the
alkyl group has 1 to 20 carbon atoms (whenever a numerical range;
e.g., "1-20", is stated herein, it means that the group, in this
case the alkyl group may contain 1 carbon atom, 2 carbon atoms, 3
carbon atoms, etc. up to and including 20 carbon atoms). More
preferably, it is a medium size alkyl having 1 to 10 carbon atoms.
Most preferably, it is a lower alkyl having 1 to 4 carbon atoms.
The alkyl group may be substituted or unsubstituted. When
substituted, the substituent group(s) is preferably one or more
individually selected from trihaloalkyl, cycloalkyl, aryl,
heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy,
heteroaryloxy, heteroalicycloxy, thiohydroxy, thioalkoxy,
thioaryloxy, thioheteroaryloxy, thioheteroalicycloxy, cyano, halo,
nitro, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl,
O-thiocarbamyl, N-thiocarbamyl, C-amido, C-thioamido, N-amido,
C-carboxy, O-carboxy, sulfinyl, sulfonyl, sulfonamido,
trihalomethanesulfonamido, trihalomethanesulfonyl, and combined, a
five- or six-member heteroalicyclic ring.
[0167] A "cycloalkyl" group refers to an all-carbon monocyclic or
fused ring (i.e., rings which share and adjacent pair of carbon
atoms) group wherein one or more rings does not have a completely
conjugated pi-electron system. Examples, without limitation, of
cycloalkyl groups are cyclopropane, cyclobutane, cyclopentane,
cyclopentene, cyclohexane, cyclohexadiene, cycloheptane,
cycloheptatriene and adamantane. A cycloalkyl group may be
substituted or unsubstituted. When substituted, the substituent
group(s) is preferably one or more individually selected from
alkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy,
heteroaryloxy, heteroalicycloxy, thiohydroxy, thioalkoxy,
thioaryloxy, thioheteroaryloxy, thioheteroalicycloxy, cyano, halo,
nitro, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl,
O-thiocarbamyl, N-thiocarbamyl, C-amido, C-thioamido, N-amido,
C-carboxy, O-carboxy, sulfinyl, sulfonyl, sulfonamido,
trihalo-methanesulfonamido, trihalomethanesulfonyl, silyl, guanyl,
guanidino, ureido, phosphonyl, amino and --NR.sup.xR.sup.y with
R.sup.x and R.sup.y as defined above.
[0168] An "alkenyl" group refers to an alkyl group, as defined
herein, consisting of at least two carbon atoms and at least one
carbon-carbon double bond.
[0169] An "alkynyl" group refers to an alkyl group, as defined
herein, consisting of at least two carbon atoms and at least one
carbon-carbon triple bond.
[0170] A "hydroxy" group refers to an --OH group.
[0171] An "alkoxy" group refers to both an --O-alkyl and an
--O-cycloalkyl group as defined herein.
[0172] An "aryloxy" group refers to both an --O-aryl and an
--O-heteroaryl group, as defined herein.
[0173] A "heteroaryloxy" group refers to a heteroaryl-O-- group
with heteroaryl as defined herein.
[0174] A "heteroalicycloxy" group refers to a heteroalicyclic-O--
group with heteroalicyclic as defined herein.
[0175] A "thiohydroxy" group refers to an --SH group.
[0176] A "thioalkoxy" group refers to both an S-alkyl and an
--S-cycloalkyl group, as defined herein.
[0177] A "thioaryloxy" group refers to both an --S-aryl and an
--S-heteroaryl group, as defined herein.
[0178] A "thioheteroaryloxy" group refers to a heteroaryl-S-- group
with heteroaryl as defined herein.
[0179] A "thioheteroalicycloxy" group refers to a
heteroalicyclic-S-- group with heteroalicyclic as defined
herein.
[0180] A "carbonyl" group refers to a --C(.dbd.O)--R" group, where
R" is selected from the group consisting of hydrogen, alkyl,
alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl (bonded through a
ring carbon) and heteroalicyclic (bonded through a ring carbon), as
each is defined herein.
[0181] An "aldehyde" group refers to a carbonyl group where R" is
hydrogen.
[0182] A "thiocarbonyl" group refers to a --C(.dbd.S)--R" group,
with R" as defined herein.
[0183] A "Keto" group refers to a --CC(.dbd.O)C-- group wherein the
carbon on either or both sides of the C.dbd.O may be alkyl,
cycloalkyl, aryl or a carbon of a heteroaryl or heteroaliacyclic
group.
[0184] A "trihalomethanecarbonyl" group refers to a
Z.sub.3CC(.dbd.O)-- group with said Z being a halogen.
[0185] A "C-carboxy" group refers to a --C(.dbd.O)O--R" groups,
with R" as defined herein.
[0186] An "O-carboxy" group refers to a R"C(--O)O-group, with R" as
defined herein.
[0187] A "carboxylic acid" group refers to a C-carboxy group in
which R" is hydrogen.
[0188] A "trihalomethyl" group refers to a --CZ.sub.3, group
wherein Z is a halogen group as defined herein.
[0189] A "trihalomethanesulfonyl" group refers to an
Z.sub.3CS(.dbd.O).sub.2-- groups with Z as defined above.
[0190] A "trihalomethanesulfonamido" group refers to a
Z.sub.3CS(.dbd.O).sub.2NR.sup.x-- group with Z and R.sup.X as
defined herein.
[0191] A "sulfinyl" group refers to a --S(.dbd.O)--R" group, with
R" as defined herein and, in addition, as a bond only; i.e.,
--S(O)--.
[0192] A "sulfonyl" group refers to a --S(.dbd.O).sub.2R" group
with R" as defined herein and, in addition as a bond only; i.e.,
--S(O).sub.2--.
[0193] A "S-sulfonamido" group refers to a
--S(.dbd.O).sub.2NR.sup.XR.sup.- Y, with R.sup.X and R.sup.Y as
defined herein.
[0194] A "N-Sulfonamido" group refers to a
R"S(.dbd.O).sub.2NR.sub.X-- group with R.sub.x as defined
herein.
[0195] A "O-carbamyl" group refers to a --OC(.dbd.O)NR.sup.xR.sup.y
as defined herein.
[0196] A "N-carbamyl" group refers to a R.sup.xOC(.dbd.O)NR.sup.y
group, with R.sup.x and R.sup.y as defined herein.
[0197] A "O-thiocarbamyl" group refers to a
--OC(.dbd.S)NR.sup.xR.sup.y group with R.sup.x and R.sup.y as
defined herein.
[0198] A "N-thiocarbamyl" group refers to a
R.sup.xOC(.dbd.S)NR.sup.y-- group with R.sup.x and R.sup.y as
defined herein.
[0199] An "amino" group refers to an --NH.sub.2 group.
[0200] A "C-amido" group refers to a --C(.dbd.)NR.sup.xR.sup.y
group with R.sup.x and R.sup.y as defined herein.
[0201] A "C-thioamido" group refers to a --C(.dbd.S)NR.sup.xR.sup.y
group, with R.sup.x and R.sup.y as defined herein.
[0202] A "N-amido" group refers to a R.sup.xC(.dbd.O)NR.sup.y --
group, with R.sup.x and R.sup.y as defined herein.
[0203] An "ureido" group refers to a
--NR.sup.xC(.dbd.O)NR.sup.yR.sup.y2 group with R.sup.x and R.sup.y
as defined herein and R.sup.y2 defined the same as R.sup.x and
R.sup.y.
[0204] An "thioureido" group refers to a
--NR.sup.xC(.dbd.S)NR.sup.yR.sup.- y2 group with R.sup.x and
R.sup.y as defined herein and R.sup.y2 defined the same as R.sup.x
and R.sup.y.
[0205] A "guanidino" group refers to a
--R.sup.xNC(.dbd.N)NR.sup.yR.sup.y2 group, with R.sup.x, R.sup.y
and R.sup.y2 as defined herein.
[0206] A "guanyl" group refers to a R.sup.xR.sup.yNC(.dbd.N)--
group, with R.sup.x and R.sup.y as defined herein.
[0207] A "cyano" group refers to a --CN group.
[0208] A "silyl" group refers to a --Si(R").sub.3, with R" as
defined herein.
[0209] A "phosphonyl" group refers to a P(.dbd.O)(OR.sup.x).sub.2
with R.sup.x as defined herein.
[0210] A "hydrazino" group refers to a --NR.sup.xNR.sup.yR.sup.y2
group with R.sup.x, R.sup.y and R.sup.y2 as defined herein.
[0211] Any two adjacent R groups may combine to form an additional
aryl, cycloalkyl, heteroaryl or heterocyclic ring fused to the ring
initially bearing those R groups.
[0212] It is known in the art that nitogen atoms in heteroaryl
systems can be "participating in a heteroaryl ring double bond",
and this refers to the form of double bonds in the two tautomeric
structures which comprise five-member ring heteroaryl groups. This
dictates whether nitrogens can be substituted as well understood by
chemists in the art. The disclosure and claims of the present
invention are based on the known general principles of chemical
bonding. It is understood that the claims do not encompass
structures known to be unstable or not able to exist based on the
literature.
[0213] Physiologically acceptable salts and prodrugs of compounds
disclosed herein are within the scope of this invention. The term
"pharmaceutically acceptable salt" as used herein and in the claims
is intended to include nontoxic base addition salts. Suitable salts
include those derived from organic and inorganic acids such as,
without limitation, hydrochloric acid, hydrobromic acid, phosphoric
acid, sulfuric acid, methanesulfonic acid, acetic acid, tartaric
acid, lactic acid, sulfinic acid, citric acid, maleic acid, fumaric
acid, sorbic acid, aconitic acid, salicylic acid, phthalic acid,
and the like. The term "pharmaceutically acceptable salt" as used
herein is also intended to include salts of acidic groups, such as
a carboxylate, with such counterions as ammonium, alkali metal
salts, particularly sodium or potassium, alkaline earth metal
salts, particularly calcium or magnesium, and salts with suitable
organic bases such as lower alkylamines (methylamine, ethylamine,
cyclohexylamine, and the like) or with substituted lower
alkylamines (e.g. hydroxyl-substituted alkylamines such as
diethanolamine, triethanolamine or
tris(hydroxymethyl)-aminomethane), or with bases such as piperidine
or morpholine.
[0214] In the method of the present invention, the term "antiviral
effective amount" means the total amount of each active component
of the method that is sufficient to show a meaningful patient
benefit, i.e., healing of acute conditions characterized by
inhibition of the HIV infection. When applied to an individual
active ingredient, administered alone, the term refers to that
ingredient alone. When applied to a combination, the term refers to
combined amounts of the active ingredients that result in the
therapeutic effect, whether administered in combination, serially
or simultaneously. The terms "treat, treating, treatment" as used
herein and in the claims means preventing or ameliorating diseases
associated with HIV infection.
[0215] The present invention is also directed to combinations of
the compounds with one or more agents useful in the treatment of
AIDS. For example, the compounds of this invention may be
effectively administered, whether at periods of pre-exposure and/or
post-exposure, in combination with effective amounts of the AIDS
antivirals, immunomodulators, antiinfectives, or vaccines, such as
those in the following table.
1 Drug Name Manufacturer Indication ANTIVIRALS 097 Hoechst/Bayer
HIV infection, AIDS, ARC (non-nucleoside reverse transcriptase (RT)
inhibitor) Amprenivir Glaxo Wellcome HIV infection, 141 W94 AIDS,
ARC GW 141 (protease inhibitor) Abacavir (1592U89) Glaxo Wellcome
HIV infection, GW 1592 AIDS, ARC (RT inhibitor) Acemannan
Carrington Labs ARC (Irving, TX) Acyclovir Burroughs Wellcome HIV
infection, AIDS, ARC, in combination with AZT AD-439 Tanox
Biosystems HIV infection, AIDS, ARC AD-519 Tanox Biosystems HIV
infection, AIDS, ARC Adefovir dipivoxil Gilead Sciences HIV
infection AL-721 Ethigen ARC, PGL (Los Angeles, CA) HIV positive,
AIDS Alpha Interferon Glaxo Wellcome Kaposi's sarcoma, HIV in
combination w/Retrovir Ansamycin Adria Laboratories ARC LM 427
(Dublin, OH) Erbamont (Stamford, CT) Antibody which Advanced
Biotherapy AIDS, ARC Neutralizes pH Concepts Labile alpha aberrant
(Rockville, MD) Interferon AR177 Aronex Pharm HIV infection, AIDS,
ARC Beta-fluoro-ddA Nat'l Cancer Institute AIDS-associated diseases
BMS-232623 Bristol-Myers Squibb/ HIV infection, (CGP-73547)
Novartis AIDS, ARC (protease inhibitor) BMS-234475 Bristol-Myers
Squibb/ HIV infection, (CGP-61755) Novartis AIDS, ARC (protease
inhibitor) CI-1012 Warner-Lambert HIV-1 infection Cidofovir Gilead
Science CMV retinitis, herpes, papillomavirus Curdlan sulfate AJI
Pharma U.S.A HIV infection Cytomegalovirus MedImmune CMV retinitis
Immune globin Cytovene Syntex Sight threatening Ganciclovir CMV
peripheral CMV retinitis Delaviridine Pharmacia-Upjohn HIV
infection, AIDS, ARC (RT inhibitor) Dextran Sulfate Ueno Fine Chem.
AIDS, ARC, HIV Ind. Ltd. (Osaka, positive Japan) asymptomatic ddC
Hoffman-La Roche HIV infection, Dideoxycytidine AIDS, ARC ddI
Bristol-Myers Squibb HIV infection, Dideoxyinosine AIDS, ARC;
combination with AZT/d4T DMP-450 AVID HIV infection, (Camden, NJ)
AIDS, ARC (protease inhibitor) Efavirenz DuPont Merck HIV
infection, (DMP 266) AIDS, ARC (-)6-Chloro-4-(S)- (non-nucleoside
RT cyclopropylethynyl- inhibitor) 4(S)-trifluoro-
methyl-1,4-dihydro- 2H-3,1-benzoxazin- 2-one, STOCRINE EL10 Elan
Corp, PLC HIV infection (Gainesville, GA) Famciclovir Smith Kline
herpes zoster, herpes simplex FTC Emory University HIV infection,
AIDS, ARC (reverse transcriptase inhibitor) GS 840 Gilead HIV
infection, AIDS, ARC (reverse transcriptase inhibitor) HBY097
Hoechst Marion HIV infection, Roussel AIDS, ARC (non-nucleoside
reverse transcriptase inhibitor) Hypericin VIMRx Pharm. HIV
infection, AIDS, ARC Recombinant Human Triton Biosciences AIDS,
Kaposi's Interferon Beta (Almeda, CA) sarcoma, ARC Interferon
alfa-n3 Interferon Sciences ARC, AIDS Indinavir Merck HIV
infection, AIDS, ARC, asymptomatic HIV positive, also in
combination with AZT/ddI/ddC ISIS 2922 ISIS Pharmaceuticals CMV
retinitis KNI-272 Nat'l Cancer Institute HIV-assoc. diseases
Lamivudine, 3TC Glaxo Wellcome HIV infection, AIDS, ARC (reverse
transcriptase inhibitor); also with AZT Lobucavir Bristol-Myers
Squibb CMV infection Nelfinavir Agouron HIV infection,
Pharmaceuticals AIDS, ARC (protease inhibitor) Nevirapine
Boeheringer HIV infection, Ingleheim AIDS, ARC (RT inhibitor)
Novapren Novaferon Labs, Inc. HIV inhibitor (Akron, OH) Peptide T
Peninsula Labs AIDS Octapeptide (Belmont, CA) Sequence Trisodium
Astra Pharm. CMV retinitis, HIV Phosphonoformate Products, Inc.
infection, other CMV infections PNU-140690 Pharmacia Upjohn HIV
infection, AIDS, ARC (protease inhibitor) Probucol Vyrex HIV
infection, AIDS RBC-CD4 Sheffield Med. HIV infection, Tech
(Houston, TX) AIDS, ARC Ritonavir Abbott HIV infection, AIDS, ARC
(protease inhibitor) Saquinavir Hoffmann- HIV infection, LaRoche
AIDS, ARC (protease inhibitor) Stavudine; d4T Bristol-Myers Squibb
HIV infection, Didehydrodeoxythymidine AIDS, ARC Valaciclovir Glaxo
Wellcome Genital HSV & CMV infections Virazole Viratek/ICN
asymptomatic HIV Ribavirin (Costa Mesa, CA) positive, LAS, ARC
VX-478 Vertex HIV infection, AIDS, ARC Zalcitabine Hoffmann-LaRoche
HIV infection, AIDS, ARC, with AZT Zidovudine; AZT Glaxo Wellcome
HIV infection, AIDS, ARC, Kaposi's sarcoma, in combination with
other therapies Tenofovir disoproxil, Gilead HIV infection,
fumarate salt (Viread .RTM.) AIDS, (reverse transcriptase
inhibitor) Combivir .RTM. GSK HIV infection, AIDS, (reverse
transcriptase inhibitor) abacavir succinate GSK HIV infection, (or
Ziagen .RTM.) AIDS, (reverse transcriptase inhibitor) REYATAZ .RTM.
Bristol-Myers Squibb HIV infection (or atazanavir) AIDs, protease
inhibitor FUZEON Roche/Trimeris HIV infection (or T-20) AIDs, viral
Fusion inhibitor IMMUNOMODULATORS AS-101 Wyeth-Ayerst AIDS
Bropirimine Pharmacia Upjohn Advanced AIDS Acemannan Carrington
Labs, Inc. AIDS, ARC (Irving, TX) CL246,738 American Cyanamid AIDS,
Kaposi's Lederle Labs sarcoma EL10 Elan Corp, PLC HIV infection
(Gainesville, GA) FP-21399 Fuki ImmunoPharm Blocks HIV fusion with
CD4+ cells Gamma Interferon Genentech ARC, in combina- tion w/TNF
(tumor necrosis factor) Granulocyte Genetics Institute AIDS
Macrophage Colony Sandoz Stimulating Factor Granulocyte
Hoechst-Roussel AIDS Macrophage Colony Immunex Stimulating Factor
Granulocyte Schering-Plough AIDS, Macrophage Colony combination
Stimulating Factor w/AZT HIV Core Particle Rorer Seropositive HIV
Immunostimulant IL-2 Cetus AIDS, in combina- Interleukin-2 tion
w/AZT IL-2 Hoffman-LaRoche AIDS, ARC, HIV, Interleukin-2 Immunex in
combination w/AZT IL-2 Chiron AIDS, increase in Interleukin-2 CD4
cell counts (aldeslukin) Immune Globulin Cutter Biological
Pediatric AIDS, in Intravenous (Berkeley, CA) combination w/AZT
(human) IMREG-1 Imreg AIDS, Kaposi's (New Orleans, LA) sarcoma,
ARC, PGL IMREG-2 Imreg AIDS, Kaposi's (New Orleans, LA) sarcoma,
ARC, PGL Imuthiol Diethyl Merieux Institute AIDS, ARC Dithio
Carbamate Alpha-2 Schering Plough Kaposi's sarcoma Interferon
w/AZT, AIDS Methionine- TNI Pharmaceutical AIDS, ARC Enkephalin
(Chicago, IL) MTP-PE Ciba-Geigy Corp. Kaposi's sarcoma
Muramyl-Tripeptide Granulocyte Amgen AIDS, in combina- Colony
Stimulating tion w/AZT Factor Remune Immune Response
Immunotherapeutic Corp. rCD4 Genentech AIDS, ARC Recombinant
Soluble Human CD4 rCD4-IgG AIDS, ARC hybrids Recombinant Biogen
AIDS, ARC Soluble Human CD4 Interferon Hoffman-La Roche Kaposi's
sarcoma Alfa 2a AIDS, ARC, in combination w/AZT SK&F106528
Smith Kline HIV infection Soluble T4 Thymopentin Immunobiology HIV
infection Research Institute (Annandale, NJ) Tumor Necrosis
Genentech ARC, Factor; TNF in combination w/gamma Interferon
[0216]
2 ANTI-INFECTIVES Drug Name Manufacturer Indication Clindamycin
with Pharmacia Upjohn PCP Primaquine Fluconazole Pfizer
Cryptococcal meningitis, candidiasis Pastille Squibb Corp.
Prevention of Nystatin Pastille oral candidiasis Ornidyl Merrell
Dow PCP Eflornithine Pentamidine LyphoMed PCP treatment Isethionate
(IM & IV) (Rosemont, IL) Trimethoprim Antibacterial
Trimethoprim/sulfa Antibacterial Piritrexim Burroughs Wellcome PCP
treatment Pentamidine Fisons Corporation PCP prophylaxis
Isethionate for Inhalation Spiramycin Rhone-Poulenc Cryptosporidial
diarrhea Intraconazole- Janssen-Pharm. Histoplasmosis; R51211
cryptococcal meningitis Trimetrexate Warner-Lambert PCP
Daunorubicin NeXstar, Sequus Kaposi's sarcoma Recombinant Human
Ortho Pharm. Corp. Severe anemia Erythropoietin assoc. with AZT
therapy Recombinant Human Serono AIDS-related Growth Hormone
wasting, cachexia Megestrol Acetate Bristol-Myers Squibb Treatment
of anorexia assoc. W/AIDS Testosterone Alza, Smith Kline
AIDS-related wasting Total Enteral Norwich Eaton Diarrhea and
Nutrition Pharmaceuticals malabsorption related to AIDS
[0217] Additionally, the compounds of the invention herein may be
used in combination with another class of agents for treating AIDS
which are called HIV entry inhibitors. Examples of such HIV entry
inhibitors are discussed in DRUGS OF THE FUTURE 1999, 24(12), pp.
1355-1362; CELL, Vol. 9, pp. 243-246, Oct. 29, 1999; and DRUG
DISCOVERY TODAY, Vol. 5, No. 5, May 2000, pp. 183-194.
[0218] It will be understood that the scope of combinations of the
compounds of this invention with AIDS antivirals, immunomodulators,
anti-infectives, HIV entry inhibitors or vaccines is not limited to
the list in the above Table, but includes in principle any
combination with any pharmaceutical composition useful for the
treatment of AIDS.
[0219] Preferred combinations are simultaneous or alternating
treatments of with a compound of the present invention and an
inhibitor of HIV protease and/or a non-nucleoside inhibitor of HIV
reverse transcriptase. An optional fourth component in the
combination is a nucleoside inhibitor of HIV reverse transcriptase,
such as AZT, 3TC, ddC or ddI. A preferred inhibitor of HIV protease
is indinavir, which is the sulfate salt of
N-(2(R)-hydroxy-1-(S)-indanyl)-2(R)-phenylmethyl-4-(S)-hydroxy-5-(1-(4-(3-
-pyridyl-methyl)-2(S)-N'-(t-butylcarboxamido)-piperazinyl))-pentaneamide
ethanolate, and is synthesized according to U.S. Pat. No.
5,413,999. Indinavir is generally administered at a dosage of 800
mg three times a day. Other preferred protease inhibitors are
nelfinavir and ritonavir. Another preferred inhibitor of HIV
protease is saquinavir which is administered in a dosage of 600 or
1200 mg tid. Preferred non-nucleoside inhibitors of HIV reverse
transcriptase include efavirenz. The preparation of ddC, ddI and
AZT are also described in EPO 0,484,071. These combinations may
have unexpected effects on limiting the spread and degree of
infection of HIV. Preferred combinations include those with the
following (1) indinavir with efavirenz, and, optionally, AZT and/or
3TC and/or ddI and/or ddC; (2) indinavir, and any of AZT and/or ddI
and/or ddC and/or 3TC, in particular, indinavir and AZT and 3TC;
(3) stavudine and 3TC and/or zidovudine; (4) zidovudine and
lamivudine and 141W94 and 1592U89; (5) zidovudine and
lamivudine.
[0220] In such combinations the compound of the present invention
and other active agents may be administered separately or in
conjunction. In addition, the administration of one element may be
prior to, concurrent to, or subsequent to the administration of
other agent(s).
Abbreviations
[0221] The following abbreviations, most of which are conventional
abbreviations well known to those skilled in the art, are used
throughout the description of the invention and the examples. Some
of the abbreviations used are as follows:
3 h = hour(s) rt = room temperature mol = mole(s) mmol =
millimole(s) g = gram(s) mg = milligram(s) mL = milliliter(s) TEA =
triethylamine TFA = Trifluoroacetic Acid DCE = 1,2-Dichloroethane
CH.sub.2Cl.sub.2 = Dichloromethane TPAP = tetrapropylammonium
perruthenate THF = Tetrahydofuran DEPBT =
3-(Diethoxyphosphoryloxy)-1,2,3-benzotriazin- 4(3H)-one DMAP =
4-dimethylaminopyridine P-EDC = Polymer supported
1-(3-dimethylaminopropyl)-3- ethylcarbodiimide EDC =
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide DMF =
N,N-dimethylformamide Hunig's Base = N,N-Diisopropylethylamine
mCPBA = meta-Chloroperbenzoic Acid azaindole = 1H-Pyrrolo-pyridine
4-azaindole = 1H-pyrrolo[3,2-b]pyridine 5-azaindole =
1H-Pyrrolo[3,2-c]pyridine 6-azaindole = 1H-pyrrolo[2,3-c]pyridine
7-azaindole = 1H-Pyrrolo[2,3-b]pyridine PMB = 4-Methoxybenzyl DDQ =
2,3-Dichloro-5,6-dicyano-1,4-be- nzoquinone OTf =
Trifluoromethanesulfonoxy NMM = 4-Methylmorpholine PIP-COPh =
1-Benzoylpiperazine NaHMDS = Sodium hexamethyldisilazide EDAC =
1-(3-Dimethylaminopropyl)-3-eth- ylcarbodiimide TMS =
Trimethylsilyl DCM = Dichloromethane DCE = Dichloroethane MeOH =
Methanol THF = Tetrahydrofuran EtOAc = Ethyl Acetate LDA = Lithium
diisopropylamide TMP-Li = 2,2,6,6-tetramethylpiperidinyl lithium
DME = Dimethoxyethane DIBALH = Diisobutylaluminum hydride HOBT =
1-hydroxybenzotriazole CBZ = Benzyloxycarbonyl PCC = Pyridinium
chlorochromate
Chemistry
[0222] The present invention comprises compounds of Formula I,
their pharmaceutical formulations, and their use in patients
suffering from or susceptible to HIV infection. The compounds of
Formula I include pharmaceutically acceptable salts thereof.
[0223] The synthesis procedures and anti-HIV-1 activities of
indoleoxoacetic ureido and thioureido piperazine containing analogs
are below. 13
[0224] Compounds of formula I can be obtained from compounds of
formula Z-W--H in the presence of a tertiary amine (3-10 eq.) such
as triethylamine or diisopropylethylamine in an anhydrous aprotic
solvent such as THF, acetonitrile or DMF at temperatures ranging
from 0.degree. C. using either a carbamoyl chloride or an
isocyanate (2-3 eq) to obtain compounds of formula I where Y is O;
or using thiocarbamoyl chloride or an isothiocyanate (2-3 eq.) to
obtain compounds of formula I where Y is S. The reaction can be
monitored by LC/MS.
[0225] The starting materials carbamoyl chlorides, isocyanates,
thiocarbamoyl chlorides and isothiocyanates can be purchased from
commercial sources (e.g. Aldrich Chemical Co.). When making
compound I where A is --NR.sup.13R.sup.14, the carbamoyl or
thiocarbamoyl chloride, 14
[0226] (where Y is O or S, and A is --NR.sup.13R.sup.14) is used.
When making compounds I where A is --NHR.sup.13, the isocyanate or
thioisocyanate, A.dbd.C.dbd.Y (where Y is O or S, and A is
--NR.sup.13) is used.
[0227] It should be noted that in many cases reactions are depicted
for only one position of an intermediate, such as the R.sup.5
position, for example. It is to be understood that such reactions
could be used at other positions, such as R.sup.2-R.sup.4, of the
various intermediates. Reaction conditions and methods given in the
specific examples are broadly applicable to compounds with other
substitution and other tranformations in this application. The
following schemes describe general reaction schemes for taking
appropriately substituted Q (indoles and azaindoles) and converting
them to compounds of Formula I. While these schemes are very
general, other permutations such as carrying a precursor or
precursors to substituents R.sup.2 through R.sup.5 through the
reaction scheme and then converting it to a compound of Formula I
in the last step are also contemplated methods of this invention.
Nonlimiting examples of such strategies follow in subsequent
schemes.
[0228] In addition to procedures for preparing Q and Z, procedures
for coupling piperazine amides to oxoacetyl derivatives are
described in the Blair, Wang, Wallace, or Wang references 93-95 and
106 respectively. The entire disclosures in U.S. Pat. No. 6,469,006
granted Oct. 22, 2002; U.S. Pat. No. 6,476,034 granted Nov. 5,
2002; U.S. patent application Ser. No. 10/027,612 filed Dec. 19,
2001, which is a continuation-in-part of U.S. Ser. No. 09/888,686
filed Jun. 25, 2001 (corresponding to PCT WO 02/04440, published
Jan. 17, 2002); and U.S. patent application Ser. No. 10/214,982
filed Aug. 7, 2002, which is a continuation-in-part of U.S. Ser.
No. 10/038,306 filed Jan. 2, 2002 (corresponding to PCT WO 02/62423
published Aug. 15, 2002) are incorporated by reference herein. The
procedures used to couple indole or azaindole oxoacetic acids to
piperazine amides in these references can be used analogously to
form the compounds of this invention except the piperazine
carbamates or thiocarbamates are used in place of the piperazine
benzamides. It should be stated that the procedures incorporated
from these applications encompass the preparation of starting
materials and transformations which are useful for enabling the
preparation of compounds of this invention.
[0229] Procedures for making Z (as defined in formula I of the
description of the invention) are described in the Blair, Wang,
Wallace, or Wang references 93-95 and 106 respectively. The entire
disclosures in U.S. Pat. No. 6,469,006 granted Oct. 22, 2002; U.S.
Pat. No. 6,476,034 granted Nov. 5, 2002; U.S. patent application
Ser. No. 10/027,612 filed Dec. 19, 2001, which is a
continuation-in-part of U.S. Ser. No. 09/888,686 filed Jun. 25,
2001 (corresponding to PCT WO 02/04440, published Jan. 17, 2002);
and U.S. patent application Ser. No. 10/214,982 filed Aug. 7, 2002,
which is a continuation-in-part of U.S. Ser. No. 10/038,306 filed
Jan. 2, 2002 (corresponding to PCT WO 02/62423 published Aug. 15,
2002) are incorporated by reference herein.
[0230] Additional general procedures to construct substituted
azaindole Q and Z of Formula I and intermediates useful for their
synthesis are described in the following Schemes. 15
[0231] Step A in Scheme 1 depicts the synthesis of an aza indole
intermediate, 2a via the well known Bartoli reaction in which vinyl
magnesium bromide reacts with an aryl or heteroaryl nitro group,
such as in 1, to form a five-membered nitrogen containing ring as
shown. Some references for the above transformation include:
Bartoli et al. a) Tetrahedron Lett. 1989, 30, 2129. b) J. Chem.
Soc. Perkin Trans. I 1991, 2757. c) J. Chem. Soc. Perkin Trans. II
1991, 657. d) Synthesis (1999), 1594. In the preferred procedure, a
solution of vinyl Magnesium bromide in THF (typically 1.0M but from
0.25 to 3.0M) is added dropwise to a solution of the nitro pyridine
in THF at -78.degree. under an inert atmosphere of either nitrogen
or Argon. After addition is completed, the reaction temperature is
allowed to warm to -20.degree. and then is stirred for
approximately 12 h before quenching with 20% aq amrnmonium chloride
solution. The reaction is extracted with ethyl acetate and then
worked up in a typical manner using a drying agent such as
anhydrous magnesium sulfate or sodium sulfate. Products are
generally purified using chromatography over Silica gel. Best
results are generally achieved using freshly prepared vinyl
Magnesium bromide. In some cases, vinyl Magnesium chloride may be
substituted for vinyl Magnesium bromide.
[0232] Substituted azaindoles may be prepared by methods described
in the literature or may be available from commercial sources. Thus
there are many methods for carrying out step A in the literature
and the specific examples are too numerous to even list. A review
on the synthesis of 7-azaindoles has been published (Merour et. al.
reference 102). Alternative syntheses of aza indoles and general
methods for carrying out step A include, but are not limited to,
those described in the following references (a-k below): a)
Prokopov, A. A.; Yakhontov, L. N. Khim. -Farm. Zh. 1994, 28(7),
30-51; b) Lablache-Combier, A. Heteroaromatics. Photoinduced
Electron Transfer 1988, Pt. C, 134-312; c) Saify, Zafar Said. Pak.
J. Pharmacol. 1986, 2(2), 43-6; d) Bisagni, E. Jerusalem Symp.
Quantum Chem. Biochem. 1972, 4, 439-45; e) Yakhontov, L. N. Usp.
Khim. 1968, 37(7), 1258-87; f) Willette, R. E. Advan. Heterocycl.
Chem. 1968, 9, 27-105; g) Mahadevan, I.; Rasmussen, M. Tetrahedron
1993, 49(33), 7337-52; h) Mahadevan, I.; Rasmussen, M. J.
Heterocycl. Chem. 1992, 29(2), 359-67; i) Spivey, A. C.; Fekner,
T.; Spey, S. E.; Adams, H. J. Org. Chem. 1999, 64(26), 9430-9443;
j) Spivey, A. C.; Fekner, T.; Adams, H. Tetrahedron Lett. 1998,
39(48), 8919-8922; k) Advances in Heterocyclic Chemistry (Academic
press) 1991, Vol. 52, pg 235-236 and references therein.
[0233] Step B. Intermediate 3a can be prepared by reaction of
aza-indole, intermediate 2a, with an excess of ClCOCOOMe in the
presence of AlCl.sub.3 (aluminum chloride) (Sycheva et al, Ref. 26,
Sycheva, T. V.; Rubtsov, N. M.; Sheinker, Yu. N.; Yakhontov, L. N.
Some reactions of 5-cyano-6-chloro-7-azaindoles and lactam-lactim
tautomerism in 5-cyano-6-hydroxy-7-azaindolines. Khim. Geterotsikl.
Soedin., 1987, 100-106). Typically an inert solvent such as
CH.sub.2Cl.sub.2 is used but others such as THF, Et.sub.2O, DCE,
dioxane, benzene, or toluene may find applicability either alone or
in mixtures. Other oxalate esters such as ethyl or benzyl mono
esters of oxalic acid could also suffice for either method shown
above. More lipophilic esters ease isolation during aqueous
extractions. Phenolic or substituted phenolic (such as
pentafluorophenol) esters enable direct coupling of the
HW-protecting group, such as a Boc-piperazine, in Step D without
activation. Lewis acid catalysts, such as tin tetrachloride,
titanium IV chloride, and aluminum chloride are employed in Step B
with aluminum chloride being most preferred. Alternatively, the
azaindole is treated with a Grignard reagent such as MeMgI (methyl
magnesium iodide), methyl magnesium bromide or ethyl magnesium
bromide and a zinc halide, such as ZnCl.sub.2 (zinc chloride) or
zinc bromide, followed by the addition of an oxalyl chloride mono
ester, such as ClCOCOOMe (methyl chlorooxoacetate) or another ester
as above, to afford the aza-indole glyoxyl ester (Shadrina et al,
Ref. 25). Oxalic acid esters such as methyl oxalate, ethyl oxalate
or as above are used. Aprotic solvents such as CH.sub.2Cl.sub.2,
Et.sub.2O, benzene, toluene, DCE, tert butyl methyl ether or the
like may be used alone or in combination for this sequence. In
addition to the oxalyl chloride mono esters, oxalyl chloride itself
may be reacted with the azaindole and then further reacted with an
appropriate amine, such as a piperazine derivative.
[0234] Step C. Hydrolysis of the methyl ester, (intermediate 3a,
Scheme 1) affords a potassium salt of intermediate 4a, which is
coupled with protected piperazine derivatives, such as
BOC-piperazine, as shown in Step D of Scheme 1. Some typical
conditions employ methanolic or ethanolic sodium hydroxide followed
by careful acidification with aqueous hydrochloric acid of varying
molarity but 1M HCl is preferred. The acidification is not utilized
in many cases as described above for the preferred conditions.
Lithium hydroxide or potassium hydroxide could also be employed and
varying amounts of water could be added to the alcohols. Propanols
or butanols could also be used as solvents. Elevated temperatures
up to the boiling points of the solvents may be utilized if ambient
temperatures do not suffice. Alternatively, the hydrolysis may be
carried out in a non polar solvent such as CH.sub.2Cl.sub.2 or THF
in the presence of Triton B. Temperatures of -78.degree. C. to the
boiling point of the solvent may be employed but -10.degree. C. is
preferred. Other conditions for ester hydrolysis are listed in
reference 41 and both this reference and many of the conditions for
ester hydrolysis are well known to chemists of average skill in the
art.
Alternative Procedures for step B and C
Imidazolium Chloroaluminate
[0235] We found that ionic liquid 1-alkyl-3-alkylimidazolium
chloroaluminate is generally useful in promoting the Friedel-Crafts
type acylation of indoles and azaindoles. The ionic liquid is
generated by mixing 1-alkyl-3-alkylimidazolium chloride with
aluminium chloride at room temperature with vigorous stirring. 1:2
or 1:3 molar ratio of 1-alkyl-3-alkylimidazolium chloride to
aluminium chloride is preferred. One particular useful imidazolium
chloroaluminate for the acylation of azaindole with methyl or ethyl
chlorooxoacetate is the 1-ethyl-3-methylimidazolium
chloroaluminate. The reaction is typically performed at ambient
temperature and the azaindoleglyoxyl ester can be isolated. More
conveniently, we found that the glyoxyl ester can be hydrolyzed in
situ at ambient temperature on prolonged reaction time (typically
overnight) to give the corresponding glyoxyl acid (intermediate 4a)
for amide formation (Scheme 2). 16
[0236] A representative experimental procedure is as follows:
1-ethyl-3-methylimidazolium chloride (2 equiv.; purchased from TCI;
weighted under a stream of nitrogen) was stirred in an oven-dried
round bottom flask at r.t. under a nitrogen atmosphere, and added
aluminium chloride (6 equiv.; anhydrous powder packaged under argon
in ampules purchased from Aldrich preferred; weighted under a
stream of nitrogen). The mixture was vigorously stirred to form a
liquid, which was then added azaindole (1 equiv.) and stirred until
a homogenous mixture resulted. The reaction mixture was added
dropwise ethyl or methyl chlorooxoacetate (2 equiv.) and then
stirred at r.t. for 16 h. After which time, the mixture was cooled
in an ice-water bath and the reaction quenched by carefully adding
excess water. The precipitates were filtered, washed with water and
dried under high vacuum to give the azaindoleglyoxylic acid. For
some examples, 3 equivalents of 1-ethyl-3-methylimidazolium
chloride and chlorooxoacetate may be required.
[0237] Related references: (1) Welton, T. Chem Rev. 1999, 99, 2071;
(2) Surette, J. K. D.; Green, L.; Singer, R. D. Chem. Commun. 1996,
2753; (3) Saleh, R. Y. WO 0015594.
[0238] Step D. The acid intermediate 4a, from step C of Scheme 1 is
coupled with a protected piperazine, for example t-butyl
1-piperazinecarboxylate (Boc-piperazine), preferably in the
presence of DEPBT
(3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one) and
N,N-diisopropylethylamine, commonly known as Hunig's base, to
provide azaindole piperazine amide (intermediate 5a). DEPBT was
either purchased from Adrich or prepared according to the procedure
of Ref. 28, Li, H.; Jiang, X.; Ye, Y. -H.; Fan, C.; Romoff, T.;
Goodman, M. Organic Lett., 1999, 1, 91-93. Typically an inert
solvent such as DMF or THF is used but other aprotic solvents could
be used. The acid intermediate 4a from Scheme 1 (which can also be
depicted as Z-OH or intermediates QC(O)C(O)OH) are coupled with
either a substituted piperazine, H--W--C(.dbd.Y)-A or a protected
piperazine, for example t-butyl 1-piperazinecarboxylate
(Boc-piperazine, H--W-tBoc), as shown in Scheme 1 (where W
corresponds to claim 1 and H is hydrogen). They can be coupled with
the acid using standard amide bond or peptide bond forming coupling
reagents. The combination of EDAC and triethylamine in
tetrahydrofuran or BOPCI and diisopropyl ethyl amine in chloroform
can be utilized most but DEPBT as mentioned above, or other
coupling reagents such as PyBop could be utilized. Another useful
coupling condition employs HATU (L. A. Carpino et. al. J. Chem.
Soc. Chem Comm. 1994, 201-203; A. Virgilio et.al. J. Am. Chem. Soc.
1994, 116, 11580-11581). A general procedure for using this reagent
is Acid (1eq) and H--W-Boc or HCl salt (2eq) in DMF are stirred at
rt for between 1 h and 2 days. HATU (2eq) was added in one portion
and then DMAP(3eq). The reaction was stirred at rt for 2 to 15 h
(reaction progress monitored by standard methods ie TLC, LC/MS).
The mixture is filtered through filter paper to collect the solid.
The filtrate is concentrated and water is added. The mixture is
filtered again and the solid is washed with water. The solid is
conbined and washed with water. Many reagents for amide bond
couplings are known by an organic chemist skilled in the art and
nearly all of these are applicable for realizing coupled amide
products.
[0239] As mentioned above, DEPBT
(3-(diethoxyphosphoryloxy)-1,2,3-benzotri- azin-4(3H)-one) and
N,N-diisopropylethylamine, commonly known as Hunig's base,
represents another efficient method to form the amide bond (step D)
and provide compounds of Claim I. DEPBT is either purchased from
Adrich or prepared according to the procedure of Ref. 28, Li, H.;
Jiang, X.; Ye, Y. -H.; Fan, C.; Romoff, T.; Goodman, M. Organic
Lett., 1999, 1, 91-93. Typically an inert solvent such as DMF or
THF is used but other aprotic solvents could be used.
[0240] Alternatively, the acid could be converted to a methyl ester
using excess diazomethane in THF/ether. The methyl ester in dry THF
could be reacted with the lithium amide of intermediate H--W. The
lithium amide of H--W, Li--W is formed by reacting intermediate 1
with lithium bistrimethylsilylamide in THF for 30 minutes in an ice
water cooling bath. Sodium or potassium amides could be formed
similarly and utilized if additional reactivity is desired. Other
esters such as ethyl, phenyl, or pentafluorophenyl could be
utilized and would be formed using standard methodology.
[0241] The amide bond construction reaction could be carried out
using the preferred conditions described above, the EDC conditions
described below, other coupling conditions described in this
application, or alternatively by applying the conditions or
coupling reagents for amide bond construction described later in
this application for construction of substituents R.sub.2-R.sub.5.
Some specific nonlimiting examples are given in this application.
In addition, the acid can be converted to the acid chloride using
oxalyl chloride in a solvent such as benzene or thionyl chloride
either neat or containing a catalystic amount of DMF. Temperatures
between 0.degree. C. and reflux may be utilized depending on the
substrate. Compounds of formula I can be obtained from the
resultant compounds of formula Z-Cl by reaction with the
appropriate H--W--C(.dbd.Y)-A in the presence of a tertiary amine
(3-10 eq.) such as triethylamine or diisopropylethylamine in an
anhydrous aprotic solvent such as dichloromethane, dichloroethane,
diethyl ether, dioxane, THF, acetonitrile, DMF or the like at
temperatures ranging from 0.degree. C. to reflux. Most preferred
are dichloromethane, dichloroethane, or THF. The reaction can be
monitored by LC/MS.
[0242] It should be noted that in many cases reactions are depicted
for only one position of an intermediate, such as the R.sup.5
position, for example. It is to be understood that such reactions
could be used at other positions, such as R.sup.2-R.sup.4, of the
various intermediates. Reaction conditions and methods given in the
specific examples are broadly applicable to compounds with other
substitution and other tranformations in this application. Schemes
1 and 2 describe general reaction schemes for taking appropriately
substituted Q (indoles and azaindoles) and converting them to
compounds of Formula I. While these schemes are very general, other
permutations such as carrying a precursor or precursors to
substituents R.sup.2 through R.sup.5 through the reaction scheme
and then converting it to a compound of Formula I in the last step
are also contemplated methods of this invention. Nonlimiting
examples of such strategies follow in subsequent schemes.
[0243] Step E. Cleaveage of the protecting group, (intermediate 5a,
scheme 1) affords piperazine 6a. Some typical conditions for the
removal of BOC employ acid such as HCl or TFA in a 1:1 mixture of
H.sub.2 O and other solvent such as THF, MeOH or acetonitrile.
Altenatively, the cleaveage can be carried out with an ahydrous
solution of 20% TFA in methylene chloride.
[0244] Step F. Carbamoylation of piperazine intermediate 6a was
carried out as described in scheme A. Therefore a solution of
intermediate 6a in anhydrous tetrahydrofuran was treated with a
carbamoyl chloride (2-3 eq.) in the presence of triethylamine (3-10
eq) at room temperature for 18 h to afford urea 7a.
[0245] The amide bond construction reactions depicted in step D of
scheme 1 could be carried out using the specialized conditions
described herein or alternatively by applying the conditions or
coupling reagents for amide bond construction described in Wallace,
reference 95. Some specific nonlimiting examples are given in this
application.
[0246] Additional procedures for synthesizing, modifying and
attaching groups are contained in references 93-95 or described
below. 17
[0247] Schemes 1 and 3 provide more specific examples of the
transformation previously described in Scheme A. Intermediates 9-15
are prepared by the methodologies as described for intermediates
1a-7a in Scheme 1. Scheme 4 is another embodiment of the
transformations described in Schemes 1 and 3. Conversion of the
phenol to the chloride (Step S, Scheme 4) may be accomplished
according to the procedures described in Reimann, E.; Wichmann, P.;
Hoefner, G.; Sci. Pharm. 1996, 64(3), 637-646; and Katritzky, A.
R.; Rachwal, S.; Smith, T. P.; Steel, P. J.; J. Heterocycl. Chem.
1995, 32(3), 979-984. Step T of Scheme 4 can be carried out as
described for Step A of Scheme 1. The bromo intermediate can then
be converted into alkoxy, chloro, or fluoro intermediates as shown
in Step U of Scheme 4. When step U is the conversion of the bromide
into alkoxy derivatives, the conversion may be carried out by
reacting the bromide with an excess of sodium methoxide in methanol
with cuprous salts, such as copper I bromide, copper I iodide, and
copper I cyanide. The reaction may be carried out at temperatures
of between ambient and 175.degree. C. but most likely will be
around 115.degree. C. or 100.degree. C. The reaction may be run in
a pressure vessel or sealed tube to prevent escape of volatiles
such as methanol. The preferred conditions utilize 3 eq of sodium
methoxide in methanol, CuBr as the reaction catalyst (0.2 to 3
equivalents with the preferred being 1 eq or less), and a reaction
temperature of 115.degree. C. The reaction is carried out in a
sealed tube or sealed reaction vessel. The conversion of the
bromide into alkoxy derivatives may also be carried out according
to procedures described in Palucki, M.; Wolfe, J. P.; Buchwald, S.
L.; J. Am. Chem. Soc. 1997, 119(14), 3395-3396; Yamato, T.; Komine,
M.; Nagano, Y.; Org. Prep. Proc. Int. 1997, 29(3), 300-303;
Rychnovsky, S. D.; Hwang, K.; J. Org. Chem. 1994, 59(18),
5414-5418. Conversion of the bromide to the fluoro derivative (Step
U, Scheme 4) may be accomplished according to Antipin, I. S.;
Vigalok, A. I.; Konovalov, A. I.; Zh. Org. Khim. 1991, 27(7),
1577-1577; and Uchibori, Y.; Umeno, M.; Seto, H.; Qian, Z.;
Yoshioka, H.; Synlett. 1992, 4, 345-346. Conversion of the bromide
to the chloro derivative (Step U, Scheme 5) may be accomplished
according to procedures described in Gilbert, E. J.; Van Vranken,
D. L.; J. Am. Chem. Soc. 1996, 118(23), 5500-5501; Mongin, F.;
Mongin, O.; Trecourt, F.; Godard, A.; Queguiner, G.; Tetrahedron
Lett. 1996, 37(37), 6695-6698; and O'Connor, K. J.; Burrows, C. J.;
J. Org. Chem. 1991, 56(3), 1344-1346. Steps V, W, X, Y and Z of
Scheme 4 are carried out according to the procedures previously
described for Steps B, C, D, E and F of Scheme 1, respectively. The
steps of Scheme 4 may be carried out in a different order as shown
in Scheme 5 and Scheme 6. 1819 2021 2223 242526
[0248] Scheme 7 shows the synthesis of 4-azaindole derivatives
2b-7b, 5-azaindole derivatives 2c-7c, and 7-azaindole derivatives
2d-7d. The methods used to synthesize 1b-5b, 1c-5c, and 1d-5d are
the same methods described for the synthesis of 1a-5a as described
in Scheme 1. It is understood, for the purposes of Scheme 7, that
1b is used to synthesize 2b-5b, 1c provides 2c-5c and 1d provides
2d-5d.
[0249] The compounds where there is a single carbonyl between the
azaindole and group W can be prepared by the method of Kelarev, V.
I.; Gasanov, S. Sh.; Karakhanov, R. A.; Polivin, Yu. N.;
Kuatbekova, K. P.; Panina, M. E.; Zh. Org. Khim 1992, 28(12),
2561-2568. In this method azaindoles are reacted with
trichloroacetyl chloride in pyridine and then subsequently with KOH
in methanol to provide the 3-carbomethoxy azaindoles shown in
Scheme 3 which can then be hydrolyzed to the acid and carried
through sequence shown in the scheme to provide the compounds of
Formula I wherein a single carbonyl links the azaindole moiety and
group W. 27
[0250] An alternative method for carrying out the sequence outlined
in steps B-D (shown in Scheme 9) involves treating an azaindole,
such as 16, obtained by procedures described in the literature or
from commercial sources, with MeMgI and ZnCl.sub.2, followed by the
addition of ClCOCOCl (oxalyl chloride) in either THF or Et.sub.2O
to afford a mixture of a glyoxyl chloride azaindole, 17a, and an
acyl chloride azaindole, 17b. The resulting mixture of glyoxyl
chloride azaindole and acyl chloride azaindole is then coupled with
mono-benzoylated piperazine derivatives under basic conditions to
afford the products of step D as a mixture of compounds, 18a and
18b, where either one or two carbonyl groups link the azaindole and
group W. Separation via chromatographic methods which are well
known in the art provides the pure 18a and 18b. Conversion of 18a
and 18b to 20a and 20b can be done following steps E and F. This
sequence is summarized in Scheme 9, below. 28 2930 31
[0251] As shown in Schemes 12 and 13, a mixture of halo-indole or
halo-azaindole intermediate, 1-2 equivalents of copper powder, with
1 equivalent preferred for the 4-F,6-azaindole series and 2
equivalents for the 4-methoxy,6-azaindole series; 1-2 equivalents
of potassium carbonate, with 1 equivalent preferred for the
4-F,6-azaindole series and 2 equivalents for the
4-methoxy,6-azaindole series; and a 2-30 equivalents of the
corresponding heterocyclic reagent, with 10 equivalents preferred;
was heated at 135-160.degree. C. for 4 to 9 hours, with 5 hours at
160.degree. C. preferred for the 4-F,6-azaindole series and 7 hours
at 135.degree. C. preferred for the 4-methoxy,6-azaindole series.
The reaction mixture was cooled to room temperature and filtered
through filter paper. The filtrate was diluted with methanol and
purified either by preparative HPLC or silica gel. In many cases no
chromatography is necessary, the product can be obtained by
crystallization with methanol.
[0252] Alternatively, the installation of amines or N linked
heteroaryls may be carried out by heating 1 to 40 equivalents of
the appropriate amine and an equivalent of the appropriate aza
indole chloride, bromide or iodide with copper bronze (from 0.1 to
10 equivalents (preferably about 2 equivalents) and from 1 to 10
equivalents of finely pulverized potassium hydroxide (preferably
about 2 equivalents). Temperatures of 120.degree. to 200.degree.
may be employed with 140-160.degree. generally preferred. For
volatile starting materials a sealed reactor may be employed. The
reaction is most commonly used when the halogen being displaced is
at the 7-position of a 6-aza or 4-azaindole but the method can work
in the 5-azaseries or when the halogen is at a different position
(4-7 position possible) As shown above the reaction can be employed
on azaindoles unsubstituted at position 3 or intermediates which
contain the dicarbonyl or the intact dicarbonyl piperazine urea or
thioureas contained in compounds of formula I.
Chemistry
[0253] All Liquid Chromatography (LC) data were recorded on a
Shimadzu LC-10 AS liquid chromatograph using a SPD-10AV UV-V is
detector with Mass Spectrometry (MS) data determined using a
Micromass Platform for LC in electrospray mode.
LC/MS Method (i.e., Compound Identification)
[0254] Note: column A is used Unless Otherwise Indicated in the
Preparation of Intermediates or Examples.
4 Column A: YMC ODS-A S7 3.0 .times. 50 mm column Column B:
PHX-LUNA C18 4.6 .times. 30 mm column Column C: XTERRA ms C18 4.6
.times. 30 mm column Column D: YMC ODS-A C18 4.6 .times. 30 mm
column Column E: YMC ODS-A C18 4.6 .times. 33 mm column Column F:
YMC C18 S5 4.6 .times. 50 mm column Column G: XTERRA C18 S7 3.0
.times. 50 mm column Gradient: 100% Solvent A/0% Solvent B to 0%
Solvent A/100% Solvent R.sub.t in min. Gradient time: 2 minutes
Hold time 1 minute Flow rate: 5 mL/min Detector 220 nm Wavelength:
Solvent A: 10% MeOH/90% H.sub.2O/0.1% Trifluoroacetic Acid Solvent
B: 10% H.sub.2O/90% MeOH/0.1% Trifluoroacetic Acid
[0255] Compounds purified by preparative HPLC were diluted in MeOH
(1.2 mL) and purified using the following methods on a Shimadzu
LC-10A automated preparative HPLC system or on a Shimadzu LC-8A
automated preparative HPLC system with detector (SPD-10A V UV-VIS)
wavelength and solvent systems (A and B) the same as above.
Preparative HPLC Method (i.e., Compound Purification)
[0256] Purification Method: Initial gradient (40% B, 60% A) ramp to
final gradient (100% B, 0% A) over 20 minutes, hold for 3 minutes
(100% B, 0% A)
5 Solvent A: 10% MeOH/90% H.sub.2O/0.1% Trifluoroacetic Acid
Solvent B: 10% H.sub.2O/90% MeOH/0.1% Trifluoroacetic Acid Column:
YMC C18 S5 20 .times. 100 mm column Detector Wavelength: 220 nm
General and Example Procedures Excerpted from Analogous Oxoacetyl
Piperazineainide Applications
[0257] The procedures described references 93-95 and 106 are
applicable example procedures for synthesizing the compounds of
formula I in this application and the intermediates used for their
synthesis. The following guidelines are illustrative but not
limiting.
[0258] The general Bartoli (vinyl Magnesium bromide) methods for
preparing functionalized indoles or azaindoles dexcribed in the
applications can be utilized for preparing new indoles or
azaindoles from the appropriate nitro aromatics or heteroaromatics
for this application. For example, in PCT/US02/00455, the general
procedure for preparing intermediate 2a (7-chloro-6-azaindole) from
2-chloro-3-nitro pyridine can be considered a general procedure
illustrating conditions which can be used to prepare azaindoles for
this application. This should be obvious since the same class of
intermdiates are needed for both inventions. Similarly, the general
procedure from the same application to prepare intermediate 3a,
Methyl (7-chloro-6azaindol-3-yl) oxoacetate, provides experimental
details for carrying our Step B of (Schemes 1-7 in this
application) Similarly, the general procedure from the same
application to prepare intermediate 4a
(Potassium(7-chloro-6azaindol-3-yl) oxoacetate, provides an example
of the general method for hydrolying oxoacteic esters (Step C of
Schemes 1-1c, 3-7). General procedures for carrying out the same
steps in the indole series are provided in references 93 and 95. An
example Bartoli reaction preparation of a functionalized indole is
given in the preparation of intermediate 1 of PCT/US01/20300 where
the preparation of 4-fluoro-7-bromo-azaindole is described from
2-fluoro-5-bromonitrobenzene- . The following Scheme provides an
example of the preparation of 4,7-dibromo-6-azaindole via an
extension of this methodology. 32
[0259] Subsequent procedures for the preparation of intermediates 2
and 3 describe procedures for adding the alkyl oxoacetate and then
for ester hydrolysis to provide the carboxylate salt and then the
carboxylic acid after acidification. Thus the chemistry described
in the incoprorated previous applications for preparing azaindole
and indole intermediates is obviously applicable since the desired
compounds are the same.
[0260] Procedures for carrying out the coupling of the indole or
azaindole oxoacetic acids to piperazine amides are described in the
references 93-95 and 106. These can also be used as procedures for
preparing the piperazine sulfonyl ureas of this invention by taking
the experimental procedures and substituting a piperazine sulfonyl
urea or mon protected piperazine in place of the piperazine amide.
This is possible because both groups have a free amine with
relatively similar activity and since the other portions of both
the piperazine benzamide and the piperizine sulfonyl urea are
relatively unreactive to many conditions, they can be installed
similarly. For example, the preparation of intermediate 4 of
PCT/US01/20300 and the preparation of intermediate 5a of
PCT/US02/00455 describe couplings of a piperazine benzamide or
methyl piperazine benzamide to an indole or azaindole oxoacetic
acid or carboxylate salt respectively. (The acid or salt can be
used interchangeably). These same procedures can be used directly
for the preparation of the compounds of this invention by
substituting the desired piperazine sulfonyl ureas for the
piperazine amides utilized in earlier applications. 3334
[0261] Once attached via a similar amide bond, both the piperazine
benzamides and the piperazine sulfonyl urea moieties are relatively
inert and thus reaction conditions used for functionalizing indoles
or azaindoles in the presence of piperazine benzamides are useful
for carrying out the same tranformations in the presence of the
piperazine sulfonyl ureas. Thus the methods and transformations
described in references 93-95 and 106 including the experimental
procedures which describe methods to functionalize the indole or
azaindole moiety in the piperazine amide series are generally
applicable for construction and functionalization of the piperazine
sulfonyl ureas of this invention. These same applications describe
general methods and specific preparations for obtaining stannane
and boronic acid reagents used for synthesizing the compounds of
formula I. 3536
[0262] where R.sup.x is as described for Scheme 7 3738
[0263] Preparati n of Example 39 from PCT/US02/00455
[0264] An example of the typical stannane/palladium coupling
procedure
[0265] where R.sup.x is as described for Scheme 7 3940
[0266] Preparation of Exampi 20 fr m PCT/US01/20300
[0267] An example to sh w h w functi nalizati n procedures of
oxoacetyl piperazin benzamides can b us d t carry ut similar tranf
rmatl ns in th corr sp nding piperidine alken s
[0268] where R.sup.x is as described for Scheme 7
PREPARATION OF INTERMEDIATES AND EXAMPLES
[0269] All starting materials, unless otherwise indicated can be
purchased from commercial sources. Methods are given for the
preparation of all intermediates.
Example 1
[0270] 41
[0271] Preparation of intermediate 1. Intermediate 1 was prepared
according to procedures described in Wallace, O. B. et al. PCT int.
appl. WO0204440, and as described in Steps A-D below. 42
[0272] A mixture of 4-fluoro-7-bromoindole (600 mg, 2.8 mmol) and
CuCN (1.004 g, 11.2 mmol) in DMF (4 ml) was refluxed for 16 hours.
After cooling to room temperature, the reaction mixture was poured
into a solution of ammonia in MeOH (30 ml, sat.) and the residue
removed by filtration. The filtrate was added to a mixture of water
(20 ml)/ammonia (20 ml, sat. aq.) and extracted with EtOAc/Ether
(1/1) until TLC analysis showed no product in the aqueous phase.
The combined organic extracts were washed with brine (2.times.200
ml) and water (200 ml), dried (MgSO.sub.4); evaporation in vacuo
gave 4-fluoro-7-cyanoindole as a tan yellow solid (310 mg, 69%).
43
[0273] To a solution of KOH (13.04 g, 0.232 mol) in 14%
H.sub.2O/EtOH (50 ml) was added 4-fluoro-7-cyanoindole (900 mg,
5.60 mmol). The resulting mixture was refluxed for 12 hours, slowly
cooled to room temperature, and concentrated in vacuo to about 30
ml. The residue was acidified to pH 2 with HCl (.about.5.5 N aq.).
The precipitate was filtered, washed with excess of water, and
dried under high vacuum to afford 4-fluoro-7-carboxyindole as a
white solid (100% conversion). The material was used without
further purification. 44
[0274] To a suspension of 4-fluoro-7-carboxyindole in a mixture of
MeOH (18 ml)/PhH (62 ml) was added (trimethylsilyl)diazomethane
(8.8 ml, 17.6 mmol, 2 M in hexane). The resulting mixture was
stirred at room temperature for 30 min., quenched with excess
acetic acid and evaporated in vacuo. The crude oily material was
purified by flash chromatography using a gradient elution (Hexane
to 10% EtOAc/Hexane) to afford 4-fluoro-7-carbomethoxy indole as a
white solid (1.04 g, 83% two steps).
Step D
[0275] Oxalyl chloride (1.2 eq.) was added dropwise to a solution
of 4-fluoro-7-carbomethoxy indole (1 eq.) prepared as described
above, in dry THF at 0.degree. C. After 5 min., the cool bath was
removed and the reaction was allowed to warm to rt and stirred
until completion determined by LCMS. The mixture was then
concentrated under reduced pressure to provide the crude oxo acetyl
chloride. Triethylamine (8.88 mmol, 1.23 mL) and 1-Boc piperazine
(7.4 mmol, 1.38 g) was added to a solution of the crude 3-oxoacetyl
chloride of 4-fluoro-7-carbomethoxy indole (7.4 mmol) in THF (70
mL) and the mixture was stirred at room temperature overnight. A
saturated aqueous solution of NaHCO.sub.3 (100 mL) was added and
then the mixture was extracted with methylene chloride (3.times.100
mL). The combined organic extracts were dried over sodium sulfate
to afford a crude containing intermediate 1. This crude
intermediate 1 was used without further purification in the next
step. MS (ESI.sup.+): 333(M+H).sup.+.
Preparation of Intermediate 2
[0276] Intermediate 1 (80 mg, 0.18 mmol) was treated with a
solution of 20%TFA in methylene chloride (2 mL) at room
temperature. After stirring for 3h, the resulting mixture was
concentrated and dried in vacuo to afford intermediate 2 which was
used in next step without further purification. MS (ESI.sup.+): 441
(M+H).sup.+.
Example 1
[0277] A THF (1 ml) solution of intermediate 2 (0.30 mmol) was
treated with triethylamine (125 .mu.l, 0.90 mmol) followed by
dimethylcarbamoyl chloride (55 .mu.l, 0.60 mmol) at room
temperature. The reaction was stirred for 16 h, then concentrated
in a rotoevaporator to afford example 1 as a pale yellow film.
.sup.1NMR (300 MHz, CDCl.sub.3): 8.11 (d, 1H, J=3.0 Hz); 7.97-7.92
(m, 1H); 7.03-6.97 (m, 1H); 3.98 (s, 3H), 3.77 (m, 2H); 3.54 (m,
2H); 3.35 (m, 2H); 3.26 (m, 2H); 2.85 (s, 6H). MS (ESI.sup.+): 405
(M+H).sup.+.
Example 2
[0278] 45
[0279] Example 1 (0.15 mmol) was treated with a solution of 40%
methylamine in water (1 mL) and the mixture was stirred at room
temperature for 3 h, then concentrated in rotoevaporator and
chromatographed on silica gel to afford the title compound as a
white solid (9.5 mg, 16% from intermediate 1). .sup.1NMR (300 MHz,
CDCl.sub.3): 8.09 (d, 1H, J=3.0 Hz); 7.42-7.39 (m, 1H); 6.97-6.91
(m, 1H); 6.55-6.45 (bs, 1H); 3.77 (m, 2H); 3.54 (m, 2H); 3.36 (m,
2H); 3.26 (m, 2H); 3.04 (d, 3H, J=5.0 Hz); 2.85 (s, 6H). MS
(ESI.sup.+): 404 (M+H).sup.+.
Example 3
[0280] 46
[0281] Example 3 was prepared in two steps from intermediate 2:
[0282] Step 1: Acylation: A THF (1 ml) solution of intermediate 2
(0.30 mmol) was treated with triethylamine (125 .mu.l, 0.90 mmol)
followed by dimethylthiocarbamoyl chloride (81 mg, 0.60 mmol) at
room temperature. The reaction was stirred for 48 h, then
concentrated in rotoevaporator to afford intermediate 3 which was
used in next step without further purification.
[0283] Step 2: Aminolysis: The crude residue of intermediate 3 from
the previous reaction was dissolved in 1 mL of MeOH and treated
with 2 mL of a 40% solution of methylamine in water. The reaction
mixture was stirred at rt for 18 h, then it was concentrated to
dryness and chromatographed in silica gel to afford the title
compound example 3 as a white solid. .sup.1NMR (300 MHz,
CDCl.sub.3): 8.11 (d, 1H, J=3.0 Hz); 7.43-7.40 (m, 1H); 6.99-6.95
(m, 1H); 6.35 (bs, 1H); 3.83 (m, 2H) 3.62-3.52 (m, 6H); 3.05 (s,
6H); 3.05 (d, 3H, J=5.0 Hz). MS (ESI.sup.+): 421 (M+H).sup.+.
Example 4
[0284] 47
[0285] Example 4 was prepared from intermediate 2 following the
procedure described for preparation example 2, using methyl,phenyl
carbamoyl chloride as the acylating agent. .sup.1NMR (300 MHz,
MeOH): 7.45-7.42 (m, 3H); 7.39-7.24 (m, 3H); 7.13 (m, 1H), 5.56
(bs, 1H); 3.30 (m, 2H); 3.21 (m, 2H); 3.18 (m, 2H); 2.98 (m, 2H);
2.66 (s, 6H);. MS (ESI.sup.+): 466 (M+H).sup.+.
Example 5
[0286] 48
[0287] Example 5 was prepared from intermediate 2 following the
procedure described for preparation example 2, using
diethylcarbamoyl chloride as the acylating agent. .sup.1NMR (500
MHz, CDCl.sub.3): 8.04 (d, 1H, J=3.0 Hz); 7.40-7.39 (m, 1H);
6.91-6.87 (m, 1H); 6.75 (bs, 1H); 3.76 (m, 2H); 3.52 (m, 2H); 3.33
(m, 2H); 3.24-3.02 (m, 6H); 3.01 (d, 3H, J=5.0 Hz); 1.12 (m, 6H).
MS (ESI.sup.+): 432 (M+H).sup.+.
Example 6
[0288] 49
[0289] Example 6 was prepared from intermediate 2 following the
procedure described for preparation example 2, using diisopropyl
carbamoyl chloride as the acylating agent. .sup.1NMR (500 MHz,
CDCl.sub.3): 8.08 (d, 1H, J=3.0 Hz); 7.42-7.39 (m, 1H); 6.97-6.91
(m, 1H); 6.55-6.45 (bs, 1H); 3.77 (m, 2H); 3.63 (m, 2H); 3.54 (m,
2H); 3.22 (m, 2H); 3.12 (m, 2H); 3.04 (d, 3H, J=5.0 Hz); 1.26 (d,
6H, J=6.5 Hz). MS (ESI.sup.+): 460 (M+H).sup.+.
Example 7
[0290] 50
[0291] Example 7 was prepared from intermediate 2 following the
procedure described for preparation example 2, using tertbutyl
isocyanate as the acylating agent. .sup.1NMR (500 MHz, CDCl.sub.3):
8.11 (d, 1H, J=3.0 Hz); 7.40-7.37 (m, 1H); 6.97-6.93 (m, 1H);
6.55-6.45 (bs, 1H); 3.77 (m, 2H); 3.54 (m, 2H); 3.49 (m, 2H); 3.39
(m, 2H); 3.05 (d, 3H, J=5.0 Hz); 1.35 (s, 9H). MS (ESI.sup.+): 432
(M+H).sup.+.
Example 8
[0292] 51
[0293] Example 8 was prepared from intermediate 2 following the
procedure described for preparation example 2, using butyl
isothiocyanate as the acylating agent. .sup.1NMR (500 MHz,
CDCl.sub.3): 8.10 (d, 1H, J=3.0 Hz); 7.42-7.39 (m, 1H); 6.97-6.91
(m, 1H); 6.55-6.45 (bs, 1H); 3.93 (m, 2H); 3.89 (m, 2H); 3.81 (m,
2H); 3.66 (m, 4H); 3.06 (d, 3H, J=5.0 Hz); 1.30-1.45 (m, 4H);
0.85-0.93 (m, 3H). MS (ESI.sup.+): 448 (M+H).sup.+.
Example 9
[0294] 52
Preparation of Intermediate 3
[0295] Intermediate 3, 4-fluoro-7-bromo-6-azaindole, was prepared
according to the following scheme: 53
[0296] Intermediate 3 was isolated as a brownish solid. MS m/z:
(M+H).sup.+ calcd for C.sub.7H.sub.5BrFN.sub.2: 214.96; found
214.97. HPLC retention time: 1.28 minutes (column G).
Preparation of Intermediate 4
[0297] To a solution of 1-ethyl-3-methyl imidazolium chloride
(2.7g, 18.6 mmol) and aluminum chloride (7.5 g, 55.8 mmol) was
added intermediate 3 (2.0 g, 9.3 mmol) followed by slow addition of
ethyloxalylacetate (2.1 ml, 18.6 mmol) at room temperature. The
reaction was then stirred at room temperature for 20 h, and
quenched by slow addition of ice water (20 mL). A light brown solid
precipitated out and collected by filtration and dried in air to
provide of intermediate 4 (2.2 g, 82%). LC/MS: (ES.sup.+) m/z
(M+H).sup.+=289. Rt=0.85 min.
Preparation of Intermediate 5
[0298] A mixture of intermediate 4 (574 mg, 2.0 mmol),
1-Boc-piperazine (1.1 g, 6.0 mmol), HOBt Hydrate (612 mg, 4.0
mmol), 1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide
hydrochloride (764 mg, 4.0 mmol) and N-methyl-morpholine (1.3 mL,
12 mmol) in DMF (15 mL) was stirred for 30 h at room temperature.
The reaction was quenched with water (20 mL). The resulting mixture
was extracted with ethylacetate (3.times.30 mL). The combined
organic layer was dried over magnesium sulfate, filtered and
concentrated. The residue was chromatographed to afford
intermediate 5 as a white powder (667 mg, 73%). .sup.1H NMR (300
MHz, CDCl.sub.3): 9.34 (bs, 1H); 8.26-8.25 (m, 1H); 8.11-8.10 (m,
1H); 3.74-3.50 (m, 8H); 1.57 (s, 9H). LC/MS: (ES.sup.+) m/z
(M+H).sup.+=457. Rt=1.43 min.
Preparation of Intermediate 6
[0299] Intermediate 5 (417 mg, 0.92 mmol) was treated with 4N HCl
in dioxane (5 mL, 20 mmol). After stirring for 15 h, the reaction
mixture was concentrated on rotoevaporator and dried in vacuo. The
resulting light yellow powder was characterized by LCMS and carried
to the next step without purification. LC/MS: (ES.sup.+) m/z
(M+H).sup.+=357. Rt=0.55 min.
Preparation of Intermediate 7
[0300] Intermediate 6 (100 mg, 0.26 mmol) was dissolved in
acetonitrile (1.5 mL) and treated with dimethylcarbamoyl chloride
(48 ul, 0.52 mmol) followed by triethylamine (100 ul, 0.78 mmol).
The reaction was stirred for 15 h at room temperature. The solid
was filtered out. The filtrate was concentrated and dried in vacuo
to provide intermediate 7 as a yellow solid which was used in the
next step without further purification. .sup.1H NMR (300MHz,
CDCl.sub.3): 10.9 (bs, 1H); 8.27-8.26 (m, 1H); 8.08-8.07 (m, 1H);
3.75-3.11 (m, 8H); 2.85 (s, 6H). LC/MS: (ES.sup.+) m/z
(M+H).sup.+=428. Rt=0.96 min.
Preparation of Compound Example 9
[0301] A mixture of intermediate 7 (100 mg, 0.22 mmol),
1,2,4-triazole (455 mg, 6.6 mmol), copper powder (14 mg, 0.22 mmol)
and potassium carbonate (30 mg, 0.22 mmol) was heated at
160.degree. C. for 7 h in a sealed tube. The reaction was cooled to
room temperature and filtered through filter paper. The filtrate
was diluted with methanol and purified by preparative HPLC to
provide the title compound. .sup.1H NMR (500 MHz, CDCl.sub.3): 9.30
(s, 1H); 8.32-8.31 (m, 1H); 8.24 (s, 1H); 8.10-8.09(m, 1H);
3.79-3.29 (m, 8H)); 3.98-3.45 (m, 8H); 2.87 (s, 6H). LC/MS: (ES+)
m/z (M+H).sup.+=415. Rt=1.01 min.
Preparation of Examples 11-14
[0302] The respective Boc piperazine amides were prepared as
described in references 93 and 95. Standard TFA deprotection
provided the corresponding QC(O)C(O)W--H (or Z-W--H) for these
three examples. Coupling with morpholine as described in Scheme A
of this application provided the compounds of Examples 11-14. More
details and a separate description of the methods used for
characterization of these compounds follow.
Preparation of Example 11
[0303] 54
[0304] Intermediates 11-A, 11-B, and 11-C were prepared as
described in the scheme above which is using the methods previously
described references 93 and 95. Standard TFA deprotection and
standard urea formation could be used to prepare the desired
example. A more detailed description of the actual procedure used
to convert 11-C to Example 11 is described below.
[0305] A well of a standard 96 well plate was loaded with 1 mL of
dichloromethane then the corresponding piperazine and then
morpholine 4-carbonyl chloride (1.1 eq, 0.0470 to 0.0532 mmol) were
then added. Next 1.1 eqs of Hunig's base (diisopropylethylamine)
were added and the plate shaken overnight at ambient temperature.
Two equivalents of PAMPS (n-propylaminomethylolystyrene, 1/mmol per
gram) were added for each equivalent of acid chloride and the
reaction mixture shaken overnight. The wells were agitated by
adding, pipetting, and re-adding 0.5 mL 10% aq citric acid about
ten times. The contents of the well was passed through anhydrous
MgSO4, and the products either used and purified by passage over
SiO2 using .about.9:1 ethylacetate: methanol or gradient.
Preparation of Examples 12
[0306] 55
[0307] Intermediates 12-A, 12-B, and 12-C were prepared as
described in the scheme above which is using the methods previously
described in references 93 and 95. Standard TFA deprotection and
standard urea formation could be used to prepare the desired
example. A more detailed description of the actual procedure used
to convert 12-C to Example 12 is described below.
[0308] A well of a standard 96 well plate was loaded with 1 mL of
dichloromethane then the corresponding piperazine and then
morpholine 4-carbonyl chloride (1.1 eq, 0.0470 to 0.0532 mmol) were
then added. Next 1.1 eqs of Hunig's base (diisopropylethylamine)
were added and the plate shaken overnight at ambient temperature.
Two equivalents of PAMPS (n-propylaminomethylolystyrene, 1/mmol per
gram) were added for each equivalent of acid chloride and the
reaction mixture shaken overnight. The wells were agitated by
adding, pipetting, and re-adding 0.5 mL 10% aq citric acid about
ten times. The contents of the well was passed through anhydrous
MgSO4, and the products either used and purified by passage over
SiO2 using .about.9:1 ethylacetate: methanol or gradient.
Preparation of Example 13
[0309] 56
[0310] Intermediate 13-A was prepared as described in the scheme
above which is using the methods previously described references 93
and 95. Standard TFA deprotection and standard urea formation could
be used to prepare the desired example. A more detailed description
of the actual procedure used to convert 13-A to Example 13 is
described below.
[0311] A well of a standard 96 well plate was loaded with 1 mL of
dichloromethane then the corresponding piperazine and then
morpholine 4-carbonyl chloride (1.1 eq, 0.0470 to 0.0532 mmol) were
then added. Next 1.1 eqs of Hunig's base (diisopropylethylamine)
were added and the plate shaken overnight at ambient temperature.
Two equivalents of PAMPS (n-propylaminomethylolystyrene, 1/mmol per
gram) were added for each equivalent of acid chloride and the
reaction mixture shaken overnight. The wells were agitated by
adding, pipetting, and re-adding 0.5 mL 10% aq citric acid about
ten times. The contents of the well was passed through anhydrous
MgSO4, and the products either used and purified by passage over
SiO2 using .about.9:1 ethylacetate: methanol or gradient.
Preparation of Examples 14
[0312] 57
[0313] Intermediates 14-A, 14-B, and 14-C were prepared as
described in the scheme above which is using the methods previously
described references 93 and 95. Standard TFA deprotection and
standard urea formation could be used to prepare the desired
example. A more detailed description of the actual procedure used
to convert 14-C to Example 14 is described below.
[0314] A well of a standard 96 well plate was loaded with 1 mL of
dichloromethane then the corresponding piperazine and then
morpholine 4-carbonyl chloride (1.1 eq, 0.0470 to 0.0532 mmol) were
then added. Next 1.1 eqs of Hunig's base (diisopropylethylamine)
were added and the plate shaken overnight at ambient temperature.
Two equivalents of PAMPS (n-propylaminomethylolystyrene, 1/mmol per
gram) were added for each equivalent of acid chloride and the
reaction mixture shaken overnight. The wells were agitated by
adding, pipetting, and re-adding 0.5 mL 10% aq citric acid about
ten times. The contents of the well was passed through anhydrous
MgSO4, and the products either used and purified by passage over
SiO2 using .about.9:1 ethylacetate: methanol or gradient.
Characterization Data for Examples 11-14
[0315] The HPLC methods used for examples 11-14 are described below
and therefore for these examples the general methods described
above are superceded by these procedures.
10 Minute HPLC Method for Examples 11-14
1. Apparatus and Reagents
1.1 Common Apparatus
[0316] 0.1 % Trifluoroacetic acid (aq)--Mobile phase "A"
[0317] 0.1 % Trifluoroacetic acid (acetonitrile)--Mobile phase
"B"
[0318] Phenomenex Luna C8 (2) 100.times.2.0 mm, 3 .mu.m column
[0319] Waters Millennium.sup.32 .TM. Chromatography Data System
(V3.2 or better)
1.2 Instrumentation
[0320] Waters 2790 LC system ("LC19"), comprising:
[0321] Waters 2790 Separations Module
[0322] Waters 2487 Dual Wavelength Absorbance Detector--wavelength
set at 215 nm.
2. Instrument Parameters
[0323] LC Conditions
Minutes
[0324] The dashed line represents re-equilibration. Overall run
time is .about.13.5 minutes, the mass spectrometer and
Millennium.sup.32 captures the first 10 minutes of the run.
6 Flow rate = 0.3 ml/min Run time = 13.5 minutes Gradient: Time
(mins) % Organic 0.00 5 6.30 95 9.50 95 9.70 5 13.5 5
3. Integration and Reporting
[0325] Data is integrated using Millennium and reported via the
Millennium software.
2.5 Minute HPLC method for Examples 41 and 42
4. Apparatus and Reagents
4.1 Common Apparatus
[0326] 0.1 % Trifluoroacetic acid (aq)--Mobile phase "A"
[0327] 0.1 % Trifluoroacetic acid (acetonitrile)--Mobile phase
"B"
[0328] Hypersil BDS C18 column 5 um, 2.1.times.50 mm
[0329] Micromass MassLynx.TM. Operating Software with OpenLynx.TM.
Browser
[0330] Option (V3.5 or better)
[0331] Waters Millennium.sup.32.TM. Chromatography Data System
(V3.2 or better)
4.2 Instrumentation
4.2.1 Micromass Single Quadrupole LCMS systems ("MS1", "MS4", "MS6"
or "MS7"), comprising:
[0332] Agilent HP1100 LC system comprising the following
modules:
[0333] G1315A Diode Array Detector or G1314A Single Wavelength UV
Detector
[0334] G1312A Binary Pump with Pulse Dampener and Mixer fitted
[0335] G1316A Vacuum Degasser (optional)
[0336] G1316A Column Oven (optional)
[0337] Polymer LabsPL1000 Evaporative Light Scattering Detector
(ELSD) with either
[0338] CTC Analytics HTC PAL Autosampler
[0339] or
[0340] Gilson 215 Single Probe Autosampler
[0341] with either
[0342] Micromass Platform LC
[0343] or
[0344] Micromass ZMD single quadrupole mass spectrometer
4.2.2 Micromass LCT systems ("MS5", "MS8" or "MS9"),
comprising:
[0345] MS5
[0346] Agilent HP1100 LC system comprising the following
modules:
[0347] G1314A Single Wavelength UV Detector
[0348] G1312A Binary Pump with Pulse Dampener and Mixer fitted
[0349] CTC Analytics HTC PAL Autosampler
[0350] Micromass LCT with Z-spray Interface
[0351] MS8
[0352] Waters 600 Binary Pump
[0353] 8.times. Waters 2487 Dual Wavelength Detector
[0354] Gilson 215 Multiprobe 8-way Autosampler
[0355] Micromass LCT with MUX.TM. 8-way interface
MS9
[0356] Waters 1525 Binary Pump
[0357] 1.times.2488 Dual Wavelength 8-way detector
[0358] CTC Analytics HTS PAL Autosampler with 4-fold injection
valve
[0359] Micromass LCT with MUX.TM. 5-way interface
5. LC Conditions
5.1.1 LC Conditions--for MS8.
[0360] Flow rate=8.0 ml/min--split 8 ways to deliver 1 ml/min
through all 8 lines
7 Time (mins) % B 0 0 1.80 95 2.10 95 2.30 0 2.90 0
5.1.2 LC Conditions--for MS9
[0361] Flow rate=4.0 ml/min--split 4 ways to deliver 1 ml/min
through all 4 lines
8 Time (mins) % B 0 0 1.80 95 2.10 95 2.30 0 2.39 0
5.2 Mass Spectrometer Conditions
[0362] Data is typically collected over the range m/z 150 to 850 at
a sampling rate of 2 scans per second (1 scan per 1.2 seconds per
line on MS8).
6. Integration and Reporting
[0363] Data is integrated using OpenLynx and reported via the
OpenLynx Browser software.
9 Exact HPLC HPLC Ret. Example # Mass Method Time Mass spec MH+,
purity Example 11 456.16 10 Min. 4.38 min. 457.31, 100% Example 12
470.14 10 Min. 6.10 min. 471.36, 100% Example 13 431.16 10 Min.
4.90 min. 432.41, 100% Example 14 528.16 10 Min. 4.36 min.. 529.28,
46%
Preparation of Compound of Example 15
[0364] 58
[0365] The compound of Example 15 was prepared from intermediate 2
following the procedure described for preparation of example 2,
using 1-Pyrrolidinecarbonyl chloride as the acylating agent.
.sup.1NMR (300 MHz, CDCl.sub.3): 8.10 (d, 1H, J=3.0 Hz); 7.42-7.39
(m, 1H); 6.97-6.93 (m, 1H); 6.45 (bs, 1H); 3.80 (m, 2H); 3.55 (m,
2H); 3.40-3.25 (m, 8H); 3.04 (d, 3H, J=5.0 Hz); 1.83 (m, 4H). MS
(ESI.sup.+): 430 (M+H).sup.+.
Biology
[0366] ".mu.M" means micromolar;
[0367] "mL" means milliliter;
[0368] ".mu.l" means microliter;
[0369] "mg" means milligram;
[0370] The materials and experimental procedures used to obtain the
results reported in Tables 1-2 are described below.
Cells
[0371] Virus production-Human embryonic Kidney cell line, 293T, was
propagated in Dulbecco's Modified Eagle Medium (Invitrogen,
Carlsbad, Calif.) containing 10% fetal Bovine serum (FBS, Sigma,
St. Louis, Mo.).
[0372] Virus infection--Human epithelial cell line, HeLa,
expressing the HIV-1 receptor CD4 was propagated in Dulbecco's
Modified Eagle Medium (Invitrogen, Carlsbad, Calif.) containing 10%
fetal Bovine serum (FBS, Sigma, St. Louis, Mo.) and supplemented
with 0.2 mg/mL Geneticin (Invitrogen, Carlsbad, Calif.).
[0373] Virus-Single-round infectious reporter virus was produced by
co-transfecting human embryonic Kidney 293 cells with an HIV-1
envelope DNA expression vector and a proviral cDNA containing an
envelope deletion mutation and the luciferase reporter gene
inserted in place of HIV-1 nef sequences (Chen et al, Ref. 41).
Transfections were performed using lipofectAMINE PLUS reagent as
described by the manufacturer (Invitrogen, Carlsbad, Calif.).
Experiment
[0374] 1. HeLa CD4 cells were plated in 96 well plates at a cell
density of 1.times.10.sup.4 cells per well in 100 .mu.l Dulbecco's
Modified Eagle Medium containing 10% fetal Bovine serum and
incubated overnight.
[0375] 2. Compound was added in a 2 .mu.l dimethylsulfoxide
solution, so that the final assay concentration would be .ltoreq.10
.mu.M.
[0376] 3. 100 .mu.l of single-round infectious reporter virus in
Dulbecco's Modified Eagle Medium was then added to the plated cells
and compound at an approximate multiplicity of infection (MOI) of
0.01, resulting in a final volume of 200 .mu.l per well.
[0377] 4. Virally-infected cells were incubated at 37 degrees
Celsius, in a CO.sub.2 incubator, and harvested 72 h after
infection.
[0378] 5. Viral infection was monitored by measuring luciferase
expression from viral DNA in the infected cells using a luciferase
reporter gene assay kit, as described by the manufacturer (Roche
Molecular Biochemicals, Indianapolis, Ind.). Infected cell
supernatants were removed and 50 .mu.l of lysis buffer was added
per well. After 15 minutes, 50 .mu.l of freshly-reconstituted
luciferase assay reagent was added per well. Luciferase activity
was then quantified by measuring luminescence using a Wallac
microbeta scintillation counter.
[0379] 6. The percent inhibition for each compound was calculated
by quantifying the level of luciferase expression in cells infected
in the presence of each compound as a percentage of that observed
for cells infected in the absence of compound and subtracting such
a determined value from 100.
[0380] 7. An EC.sub.50 provides a method for comparing the
antiviral potency of the compounds of this invention. The effective
concentration for fifty percent inhibition (EC.sub.50) was
calculated with the Microsoft Excel Xlfit curve fitting software.
For each compound, curves were generated from percent inhibition
calculated at 10 different concentrations by using a four
paramenter logistic model (model 205). The EC.sub.50 data for the
compounds is shown in Table 2. Table 1 is the key for the data in
Table 2.
Results
[0381]
10TABLE 1 Biological Data Key for EC.sub.50s Compounds* with
Compounds with Compounds with EC.sub.50s > 5 .mu.M EC.sub.50s
> 1 .mu.M but < 5 .mu.M EC.sub.50 < 1 .mu.M Group C Group
B Group A
[0382] *Some of these compounds may have been tested at a
concentration lower than their EC.sub.50 but showed some ability to
cause inhibition and thus should be evaluated at a higher
concentration to determine the exact EC.sub.50.
[0383] In Table 2, X.sub.z, X.sub.a and X.sub.w indicate the point
of attachment.
11TABLE 2 59 Examples EC.sub.50 Table Entry Group (Example from
Number.) Z W Y A Table 1 1 (Example 1) 60 61 O 62 B 2 (Example 2)
63 64 O 65 A 3 (Example 3) 66 67 S 68 A 4 (Example 4) 69 70 O 71 B
5 (Example 5) 72 73 O 74 B 6 (Example 6) 75 76 O 77 C 7 (Example 7)
78 79 O 80 C 8 (Example 8) 81 82 S 83 C 9 (Example 9) 84 85 O 86 A
10 (Example 10, intermediate 7) 87 88 O 89 A 11 (Example 11) 90 91
O 92 B 12 (Example 12) 93 94 O 95 13 (Example 13) 96 97 O 98 14
(Example 14) 99 100 O 101 15 (Example 15) 102 103 O 104 B
[0384] The compounds of the present invention may be administered
orally, parenterally (including subcutaneous injections,
intravenous, intramuscular, intrasternal injection or infusion
techniques), by inhalation spray, or rectally, in dosage unit
formulations containing conventional non-toxic pharmaceutically
acceptable carriers, adjuvants and diluents.
[0385] Thus, in accordance with the present invention, there is
further provided a method of treating and a pharmaceutical
composition for treating viral infections such as HIV infection and
AIDS. The treatment involves administering to a patient in need of
such treatment a pharmaceutical composition comprising a
pharmaceutical carrier and a therapeutically effective amount of a
compound of the present invention.
[0386] The pharmaceutical composition may be in the form of orally
administrable suspensions or tablets; nasal sprays, sterile
injectable preparations, for example, as sterile injectable aqueous
or oleagenous suspensions or suppositories.
[0387] When administered orally as a suspension, these compositions
are prepared according to techniques well known in the art of
pharmaceutical formulation and may contain microcrystalline
cellulose for imparting bulk, alginic acid or sodium alginate as a
suspending agent, methylcellulose as a viscosity enhancer, and
sweetners/flavoring agents known in the art. As immediate release
tablets, these compositions may contain microcrystalline cellulose,
dicalcium phosphate, starch, magnesium stearate and lactose and/or
other excipients, binders, extenders, disintegrants, diluents, and
lubricants known in the art.
[0388] The injectable solutions or suspensions may be formulated
according to known art, using suitable non-toxic, parenterally
acceptable diluents or solvents, such as mannitol, 1,3-butanediol,
water, Ringer's solution or isotonic sodium chloride solution, or
suitable dispersing or wetting and suspending agents, such as
sterile, bland, fixed oils, including synthetic mono- or
diglycerides, and fatty acids, including oleic acid.
[0389] The compounds of this invention can be administered orally
to humans in a dosage range of 1 to 100 mg/kg body weight in
divided doses. One preferred dosage range is 1 to 10 mg/kg body
weight orally in divided doses. Another preferred dosage range is 1
to 20 mg/kg body weight in divided doses. It will be understood,
however, that the specific dose level and frequency of dosage for
any particular patient may be varied and will depend upon a variety
of factors including the activity of the specific compound
employed, the metabolic stability and length of action of that
compound, the age, body weight, general health, sex, diet, mode and
time of administration, rate of excretion, drug combination, the
severity of the particular condition, and the host undergoing
therapy.
* * * * *